Invasive Bladder Transitional Cell Carcinoma OBJECTIVES

Transcription

1 Invasive Bladder Transitional Cell Carcinoma UBC Urology Grand Rounds 7 September 2005 John Morrell R5 OBJECTIVES Review role of lymphadenectomy Review role of chemotherapy Review results of bimodal bladder preservation protocols 1

2 OUTLINE Introduction Role of lymphadenectomy in radical cystectomy Neoadjuvant chemotherapy Adjuvant chemotherapy Chemotherapy for M+ disease Bladder Preservation INTRODUCTION Campbell s 8 th Majority of newly diagnosed have superficial TCC ( T1, confined to LP and urothelium) 20 40% will present with or develop invasive disease ( ( T2, muscle invasion) Surgery is gold standard treatment for invasive disease: Males radical cystoprostatectomy Females anterior exenteration 2

3 Good results Why surgery? Excellent local control Lowest pelvic recurrence rates Best long term survival Stein J Clin Oncol 2001;19: 666 Acceptable M&M TCC is resistant to radiation even at high doses Why Surgery? AUAU 23:21, 2004 Chemo alone or in combo with bladder sparring protocols has not demonstrated equivalent long-term survival Surgery provides accurate pathological staging of the primary and regional lymph nodes appropriate adjuvant therapy 3

4 ROLE OF LYMPHADENECTOMY Survey Role of Lymphadenectomy TCC progressively invade from mucosa LP muscularis propria fat contiguous organs Increasing incidence of lymph node involvement at each depth of invasion Std LND: removes nodes of distal common iliac, ext iliac, int iliac, and obturator Extended LND: IMA and down 4

5 Lymph Node Mets at Autopsy Initial belief lymphadenopathy = death Colston & Leadbetter,, JU autopsy cases of bladder cancer Pelvic or retroperitoneal met involvement only in 25% Jewett & Strong, JU autopsy cases of bladder cancer cardinal site of mets,, percentage of extravesical tumours had mets confined to pelvic nodes Bottom line: some have regional nodal mets only that can be removed with appropriate LND cure Lymphatic Drainage of Bladder Drainage from bladder AUAU 23:21, Visceral lymphatic plexus in bladder wall 2. Juxtavesical nodes in perivesical fat 3. Pelvic collecting trunks medial to int/ext iliac nodes 4. Regional nodes (int/ext iliac & sacral nodes) 5. Lymphatic trunks from regional nodes 6. Common iliac nodes and up 5

6 Impact of Number of Nodes Sampled Leissner, BJU 2000; 85:817 More nodes removed survival Retrospective review of 302 rad cystectomies Indications: Tis T4 Mean f/u: ~ 3 yrs (39 months) Mean number of nodes removed: different pathologist: no difference in number identified by each Impact of Number of Nodes Sampled Leissner, BJU 2000; 85:817 % pn+ + greater if 16 nodes recovered (pt3 and pt4 only) Cumulative % of cases with nodal mets correlated with number of nodes recovered 6

7 Impact of Number of Nodes Sampled # Nodes removed 15 5 yr pelvic recurrence 27% 5 yr distant recurrence 17% 16 17% 10.5% Leissner, BJU 2000; 85:817 Impact of Number of Nodes Sampled Herr JU 2002; 167: 1295 Similar results 322 patients followed for min 10 yrs 258 (80%) pn0, 64 (20 %) pn+ Survival of pn0 patients by number of nodes examined, 8 nodes was median 7

8 Impact of Number of Nodes Sampled Herr JU 2002; 167: 1295 Survival of pn+ patients by number of nodes examined, 11 nodes was median Impact of Number of Nodes Sampled Herr Urology 2003; 61: patients followed for min 5 yrs 489 (77%) pn0, 148 (23%) pn+ 8

9 Impact of Number of Nodes Sampled Herr Urology 2003; 61:105 pn0 pn+ Impact of Number of Nodes Sampled Herr BJU 2003; 92:187 Factors involved in survival with nodes removed: More complete LND wider margin and diminished local recurrence More complete LND diminished regional recurrence More accurate staging appropriate adjuvant chemo 9

10 Impact of Number of Nodes Sampled Konety JU 2003; 169: 946 More evidence for more nodes Data from NCI Surveillance, Epidemiology, and End Results (SEER) program SEER records all cases of cancer diagnosed in 9 geographic areas of US 1923 cystectomies from 1988 on with minimum 2 yr f/u Included those who received chemo, radiation Impact of Number of Nodes Sampled Konety JU 2003; 169:

11 Impact of Number of Nodes Sampled Konety JU 2003; 169: 946 Stage III: invasion of perivesical tissue with no regional nodal or distant mets (i.e. N0, M0) Impact of Number of Nodes Sampled Konety JU 2003; 169: 946 Stage IV: N+, M+, or invasion of adjacent structures 11

12 Impact of Number of Nodes Sampled Konety JU 2003; 169: 946 Maximum survival advantage seen when > nodes removed regardless of primary tumour stage Recommend excision of nodes routinely at cystectomy Factors Influencing Number of Nodes Sampled Boundaries of LND How specimen is submitted (en bloc vs separate packets) Pathologist diligence in searching for and preparing nodes for histologic evaluation AUAU 2004; 23:21 12

13 Boundaries of LND Std LND: removes nodes of distal common iliac, ext iliac, int iliac, and obturator Yield: ~ Extended LND: IMA and down Yield: ~ 40 Herr BJU 2003; 92:187 Extended LND Leissner, JU 2004; 171: 139 Extent of LND varies among institutions No UICC defined minimum number of nodes to be examined Not known exactly how often nodal mets occur in different locations Not known which nodes must be excised to remove all nodal mets 13

14 Extended LND Leissner, JU 2004; 171: 139 Prospective analysis of nodal mets 290 cystectomies with extended LND, T2 6 different institutions, 12 surgeons total Boundaries: IMA, genitofemoral nerve, pelvic floor Avg 43 nodes removed, 28% pn+ No significant adverse outcomes ~ 60 min more time for LND but less for Cx Extended LND Leissner, JU 2004; 171: , 12: deep obturator space, extends up to origin of obturator nerve 14

15 Extended LND Leissner, JU 2004; 171: 139 Results of Extended LND Poulsen, JU 1998; 160:2015 Extending the LND makes a difference 1 surgeon s s results of 196 cases First 68: LND confined to bifurcation of common iliacs down Second 126: LND from bifurcation of aorta down No adjuvant therapy used Surgeon experience: no difference in outcomes between first and last half 15

16 Results of Extended LND Poulsen, JU 1998; 160:2015 Results of Extended LND Results of Extended LND Poulsen, JU 1998; 160:

17 Results of Extended LND Poulsen, JU 1998; 160:2015 pn0 Results of Extended LND Herr BJU 2003 More support for extended LND Analysis of prospective neoadjuvant MVAC trial data (NEJM 2003) 270 had cystectomy 24 had no LND 98 had limited LND of obturator fossa 146 had standard pelvic node dissection (iliac bifurcation down) 17

18 Results of Extended LND Herr BJU 2003 Median number of nodes removed: 10 Extent of LND 5-yr Survival None Obturator fossa Standard (iliac bifurcation) 33% 46% 60% Results of Extended LND Herr BJU 2003 Multivariate analysis of factors influencing survival: Extent of node dissection Number of nodes removed Number of cases performed by individual surgeon These surgical factors were most important predictors of outcome, not chemo 18

19 Results of Extended LND: M&M Many undergoing radical cystectomy are elderly Many have significant comorbidity Can they tolerate extended LND? Yes. Results of Extended LND: M&M Brossner BJU 2004; 93:64 92 consecutive radical cystectomies ASA 2 3 Ileal conduit in 58, ileal neobladder in 34 Mean age: late 60 s Group A: Cystectomy + limited LND (perivesical & obturator fossa nodes) Group B: Cystectomy + extended LND (IMA down) 19

20 Results of Extended LND: M&M Brossner BJU 2004; 93:64 30 day f/u LMWH + compressive stockings started 1 day preop Broad spectrum Abx started preop Equal transient, insignificant intraop medical disturbances in both OR time (median): 277 vs 330 (diff 63) Results of Extended LND: M&M Brossner BJU 2004; 93:64 Hospital stay: equivalent Return to OR: equivalent Mean blood transfusions: 3.2 vs 0.7 (p =0.07) Deaths: 2 in limited LND group from pneumonia, 1 in extended LND group from PE 20

21 Results of Extended LND: M&M Brossner BJU 2004; 93:64 B is extended LND group Results of Extended LND: M&M Despite prolonging operation, extended LND didn t periop complications Others found similarly: Poulsen JU 98: no lymph comps Leissner BJU 00: no lymph comps Leissner JU 04: no lymph comps Brossner BJU 2004; 93:64 21

22 Factors Influencing Number of Nodes Sampled Boundaries of LND How specimen is submitted (en bloc vs separate packets) Pathologist diligence in searching for and preparing nodes for histologic evaluation AUAU 2004; 23:21 Separate vs. En Bloc LND 36 patients 20 had standard LND Left side nodes submitted separately Right side nodes submitted en bloc with bladder 12 had extended LND Bochner JU 2001; 166: had nodes submitted in separately 6 had en bloc resection 22

23 Separate vs. En Bloc LND Bochner JU 2001; 166: 2295 Routine methods of gross and microscopic examination Nodes identified by inspection and palpation No clearing solutions used Multiple pathologists Separate vs. En Bloc LND Bochner JU 2001; 166: 2295 Mean differences statistically significant, t test p =

24 Separate vs. En Bloc LND Extended LND, mean number of nodes En bloc: 22.6 Separate packets: 36.5 Bochner JU 2001; 166: 2295 Conclusion: nodes should be submitted in packets rather than en bloc Easier for pathologist to identify nodes less under staging and more appropriate use of adjuvant chemo Halfway there Getting ready for a typical day in the OR at SPH 24

25 Halfway there Final Score: John 1 Cock ring 0 Factors Influencing Number of Nodes Sampled Boundaries of LND How specimen is submitted (en bloc vs separate packets) Pathologist diligence in searching for and preparing nodes for histologic evaluation AUAU 2004; 23:21 25

26 Role of the Pathologist Herr Cancer 2002; 95: 668 General guidelines exist for pathological evaluation of cancer specimens No widely accepted practice standards for LN examination in cystectomy specimens Determining node status is essential for treatment decisions (adjuvant chemo or not) Role of the Pathologist Herr Cancer 2002; 95: 668 Recommendations: Careful dissection of all fat/packets Visual enhancement (fat clearing) techniques probably not necessary Examination of both halves of node if first half is negative Reporting of number of nodes examined, involved with tumour,, and size Examine 9 14 nodes Issue for quality assurance review 26

27 LND: The Bottom Line Issues in interpreting these studies: Upstaging by more thorough path exam Stage migration from more extensive LND Majority of pn+ + patients still die of mets LND: The Bottom Line Number of nodes removed relates to completeness of LND Extent of LND has prognostic significance for pn0 and pn+ + cases Extended LND (pn( pn- and pn+ + disease) may remove undetected nodal mets survival Limits of LND still undefined 27

28 LND: The Bottom Line Recommended limits of LND Herr BJU 2003 Proximally: distal para-aortic aortic and paracaval Distally: pelvic floor and node of cloquet Laterally: genitofemoral nerve Medially: presacral nodes NEOADJUVANT CHEMO Survey 28

29 Neoadjuvant Chemotherapy Rosenberg, JU 2005; 174:14 Most with recurrence have distant mets,, occult micromets at cystectomy Chemo may have role in distant mets Why neoadjuvant instead of adjuvant: Down staging easier & better surgery No waiting for post-op op recovery Better tolerated pre-op Various neoadjuvant regimens evaluated Single agent therapy appears useless Neoadjuvant Chemotherapy MRC/EORTC, Lancet 2003; 354:533 T2 T4a patients, tumour < 7 cm, N0/x x 21 day cycles neoadjuvant methotrexate, vinblatine,, cisplatin 200 alive at min 3 yrs f/u, median 4 yrs 485 cystectomy or full dose EBRT alone 107 alive at min 3 yrs f/u, median 4 yrs 20 countries, 106 institutions Intention to treat analysis, powered to detect 10% survival, 90%, type I error 5% 29

30 Neoadjuvant Chemotherapy MRC/EORTC, Lancet 2003; 354:533 13% in risk of locoregional recurrence or death 5% locoregional recurrence-free 3 yrs Median locoregional recurrence-free survival of 3.5 months (23.5 vs 20) Neoadjuvant Chemotherapy MRC/EORTC, Lancet 2003; 354:533 21% in risk of mets or death 8% mets-free 3 yrs Median mets-free survival of 7 months (32 vs 25) 30

31 Neoadjuvant Chemotherapy MRC/EORTC, Lancet 2003; 354:533 18% in risk of recurrence, mets or death 7% disease-free 3 yrs Median disease-free survival of 3.5 months (20 vs 16.5) Neoadjuvant Chemotherapy MRC/EORTC, Lancet 2003; 354:533 15% in risk of death 5.5% 3 yrs ( ) *updated results found this to be significant Median survival of 6.5 months (44 vs 37.5) 31

32 Neoadjuvant Chemotherapy MRC/EORTC, Lancet 2003; 354:533 Limitations of study Extent of surgery, LND, EBRT not standardized No restrictions on salvage therapy (36%) Conclusion: neoadjuvant MVP possible modest survival Neoadjuvant Chemotherapy SWOG, NEJM 2003; 349: 859 T2 T4a patients, N0M0, 8 yrs f/u median x 28 day cycles neoadjuvant methotrexate,, vinblastine, doxorubicin, cisplatin (M-VAC) then cystectomy median 115 days post randomization 154 cystectomy and bilat pelvic LND 126 institutions Powered to detect 50% median survival, 80%, type I error 5%, intention to treat 32

33 Neoadjuvant Chemotherapy SWOG, NEJM 2003; 349: 859 Neoadjuvant Chemotherapy SWOG, NEJM 2003; 349:

34 Neoadjuvant Chemotherapy SWOG, NEJM 2003; 349: 859 The case for neoadjuvant rather than adjuvant chemo Neoadjuvant Chemotherapy SWOG, NEJM 2003; 349: 859 No significant differences between the 2 groups in rates and severity of post-op complications 34

35 Neoadjuvant Chemotherapy SWOG, NEJM 2003; 349: 859 M-VAC didn t t adversely affect chance of undergoing cystectomy Estimated risk of death reduced by 33% Survival benefit appears to be related to downstaging of tumour to pt0 38% of neoadjuvants were pt0 vs 15% of cystectomy alone patients Neoadjuvant Chemotherapy Winquist, JU 2004; 171: 561 Systematic review & meta-analysis analysis of all known RCTs of neoadjuvant chemo for T2 T4a, N0/x TCC 16 RCTs identified, 11 with suitable survival data (2605 patients) 8 RCTs were of cisplatin based combination chemo 35

36 Neoadjuvant Chemotherapy Winquist, JU 2004; 171: 561 Neoadjuvant Chemotherapy Winquist, JU 2004; 171: 561 Pooled HR from 8 combination chemo RCTs: : 0.87 (95% CI ) 13% in risk of death 6.5% absolute improvement in overall survival 36

37 Neoadjuvant Chemotherapy: bottom line modest survival Does not negatively impact surgical outcome Appropriate to offer neoadjuvant chemo to every surgical candidate with muscle invasive TCC ADJUVANT CHEMOTHERAPY Rosenberg, JU 174: 14, 2005 Arguments for adjuvant rather than neoadjuvant chemo Earlier cystectomy Tumour debulking without delay of preop chemo Ability to risk stratify patients by more accurate pathological staging Several small RCTs have addressed issue 37

38 Adjuvant Chemotherapy Skinner, JU 145: 459, patients, pt3 4, and/or pn+ Randomized to adjuvant combo chemo (cisplatin, cyclophosphamide,, and doxorubicin) ) or observation Time to progression: 6.58 yrs vs yrs 5-yr survival: no significant difference Adjuvant Chemotherapy Freiha,, JU 155: 495, patients, pt3 4, pn+ + or pn- Randomized to 4 cycles cisplatin, methotrexate,, and vinblastine adjuvantly or at relapse Stopped early due to TTP benefit Overall survival not improved 38

39 Adjuvant Chemotherapy Stockle,, JU 148: 302, patients, pt3b 4a, and/or pn+ Randomized to adjuvant MVAC, MVEC or observation Stopped early due to disease free survival 5 yr disease free survival: 50% vs. 22% (p = 0.002) Adjuvant Chemotherapy Rosenberg, JU 174: 14, 2005 Adjuvant therapy remains unproven Small underpowered studies Appears to TTP if not survival Chemo at relapse known to survival, may explain apparent equivalent survival Adjuvant chemo widely used nonetheless 39

40 CHEMOTHERAPY FOR M+ DISEASE von der Maase,, J Clin Oncol 23: 4602, 2005 MVAC has been the std therapy for advanced TCC Toxicity limits MVAC usefulness GC is new std of care Chemotherapy for M+ Disease von der Maase,, J Clin Oncol 23: 4602, patients, locally advanced or M+ 203 randomized to gemcitabine/cisplatin 202 randomized to MVAC At time of analysis: 347 dead 40

41 Chemotherapy for M+ Disease von der Maase,, J Clin Oncol 23: 4602, 2005 No statistically significant difference in: Overall survival Median survival 5-yr survival Progression free survival Chemotherapy for M+ Disease von der Maase,, J Clin Oncol 18: 3068, 2000 Equal quality of life Toxic death rate: GC 1% vs. 3% MVAC Better weight maintenace,, performance status, and fatigue with GC Overall, better risk benefit new std of care 41

42 BLADDER PRESERVATION Bimodal preservation: chemo and TURBT/partial cystectomy Trimodal preservation: chemo, radiation, radical TURBT/partial cystectomy Come back Nov 30, 2005 Bladder Preservation: bimodal Sternberg,, Cancer 97: 1644, 2003 Idea based on finding of significant number of patients who are pt0, pn0 after neoadjuvant chemo then cystectomy 104 patients, clinical T2 4, N0M0 3 cycles neoadjuvant MVAC, restaging (TURBT + CT) then: Surveillance (52, 10% cystectomy) partial cystectomy and surveillance (13, 23% cystectomy) Radical cystectomy (39) 42

43 Bladder Preservation: bimodal Sternberg,, Cancer 97: 1644, 2003 Criteria for bladder preservation: CR or PR to neoadjuvant chemo (MSKCC) Solitary lesion in favourable location No prior TCC No cis Good bladder capacity Bladder Preservation: bimodal Sternberg,, Cancer 97: 1644,

44 Bladder Preservation: bimodal Sternberg,, Cancer 97: 1644, 2003 Survival according to treatment Bladder Preservation: bimodal Sternberg,, Cancer 97: 1644, 2003 Survival according to restaging TURBT 44

45 Bladder Preservation: bimodal Sternberg,, Cancer 97: 1644, 2003 Similar results to contemporary cystectomy series Comparing results is confounded by discordance b/w clinical and path staging Likely feasible alternative in select patients Needs confirmation in prospective RCT Radical cystectomy remains gold std Extended LND Neoadjuvant chemo DISCUSSION 45