Neoadjuvant and Adjuvant Chemotherapy in Bladder Cancer

Transcription

1 Neoadjuvant and Adjuvant Chemotherapy in Bladder Cancer Neal D. Shore, MD,FACS Carolina Urologic Research Center Myrtle Beach South Carolina IBCU, 2017

2 Alan Yagoda, MD New York Times :Obituary Dr. Alan Yagoda, an oncologist who specialized in genito- urinary cancer research and contributed a new treatment for metastanc bladder tumors, died on Saturday,August 23, 1995 at Columbia Medical Center. He was 60 and lived in Pleasantville, N.Y. At his death, Dr. Yagoda was professor of clinical medicine and avending physician at the medical center's medical oncology division. He joined the Columbia staff in 1991 azer working at the Cornell University College of Medicine, Memorial Sloan- KeVering Cancer Center and Yale University Medical School. At Memorial Sloan- KeVering, he served as chief of its solid- tumor service in the 1980's. There, he developed and tested a four- drug chemotherapy program known as M- VAC that resulted in significant shrinkage of metastanc bladder cancer in two- thirds of panents. His treatment became a standard therapy.

3 Alan Yagoda, MD New York Times :Obituary Dr. Alan Yagoda, an oncologist who specialized in genito- urinary cancer research and contributed a new treatment for metastanc bladder tumors, died on Saturday,August 23, 1995 at Columbia Medical Center. He was 60 and lived in Pleasantville, N.Y. At his death, Dr. Yagoda was professor of clinical medicine and avending physician at the medical center's medical oncology division. He joined the Columbia staff in 1991 azer working at the Cornell University College of Medicine, Memorial Sloan- KeVering Cancer Center and Yale University Medical School. At Memorial Sloan- KeVering, he served as chief of its solid- tumor service in the 1980's. There, he developed and tested a four- drug chemotherapy program known as M- VAC that resulted in significant shrinkage of metastanc bladder cancer in two- thirds of panents. His treatment became a standard therapy.

4 E.DarracoV Vaughn,MD New York Times Obituary April 25,2016 VAUGHAN- - E. DarracoV Jr., NewYork- The James J. Colt Professor of Urology, Dr. Vaughan was the first chairman of Department of Urology New York Hospital and it rose to nanonal prominence under his leadership from Recognized as a leading authority in his field, he achieved many research and clinical breakthroughs in renovascular hypertension, renal physiology and genitourinary surgery. He served as president of the American Urological AssociaNon, the American FoundaNon for Urologic Diseases and the American Board of Urology. For his remarkable contribunons to the field, he received numerous presngious awards.

5 E.DarracoV Vaughn,MD New York Times Obituary April 25,2016 VAUGHAN- - E. DarracoV Jr., NewYork- The James J. Colt Professor of Urology, Dr. Vaughan was the first chairman of Department of Urology New York Hospital and it rose to nanonal prominence under his leadership from Recognized as a leading authority in his field, he achieved many research and clinical breakthroughs in renovascular hypertension, renal physiology and genitourinary surgery. He served as president of the American Urological AssociaNon, the American FoundaNon for Urologic Diseases and the American Board of Urology. For his remarkable contribunons to the field, he received numerous presngious awards.

6 Mul$disciplinary Team OpNmal management of advanced bladder cancer requires a mulndisciplinary approach involving coordinanon of care between: PaNent, family Urologist, urologic oncologist Medical oncologist Pathologist, radiologist SupporNve care/nursing Lack of good communicanon during course of adjuvant chemotherapy can result in delayed cystectomy 1 PaNents who parncipate in their treatment decisions: Report feeling informed, empowered more ozen than those who do not Express higher levels of sansfacnon with medical care Report bever quality of life 2 1. Cowan NG et al. Adv Urol. 2014;2014: Makarov DV et al. Shared decision making into urological pracnce. 6

7 Efficacy of Radical Cystectomy Excellent and unparalleled local control Most effective rates of cure 5-year disease-free survival rates: Organ confined P2: 65-85% Extravesical P3a/P3b: 35-65% Node Positive (N+): 30% Even with RC, up to 35% will die of disease

8 Outcomes of Radical Cystectomy USC/Norris Cancer Center Experience 1.00 Probability of Not Recurring P <0.001 Organ Confined (n=594) Extraves ical (n=214) Lymph Node (+) (n=246) Stein JP et al: J Clin Oncol 2001; 19:666-75

9 Optimizing perioperative systemic therapy in MIBC Disconnect between Efficacy and EffecNveness Limited Level I Evidence Poor Understanding of Disease Pathogenesis and TherapeuNc Targets

10 Optimizing perioperative systemic therapy in MIBC Disconnect between Efficacy and EffecNveness Limited Level I Evidence Poor Understanding of Disease Pathogenesis and TherapeuNc Targets

11 ct2-t4a Bladder Cancer Perioperative chemotherapy is intended to eradicate subclinical disease and improve overall survival Options for Muscle Invasive UCC Radical Cystectomy (RC) Neoadjuvant Chemotherapy + RC RC + Adjuvant Chemotherapy Bladder Sparing Strategies

12 Neoadjuvant Chemotherapy Advantages: More fit for therapy Assess primary tumor = prognostic significance Consideration of organ preservation Disadvantages: Marked discordance pathologic/clinical staging

13 SelecNng PaNents for Neoadjuvant Chemotherapy CisplaNn- based, neoadjuvant chemotherapy recommended for panents with clinical stage T2 MIBC or higher PaNents who should not receive cisplann- based chemotherapy: Renal impairment or other comorbidines, such as cardiac disease Poor performance status ( ECOG score 2) NaNonal Comprehensive Cancer Network (NCCN). NCCN Clinical PracNce Guidelines in Oncology: Bladder Cancer. Version professionals/physician_gls/pdf/bladder.pdf. Accessed 10/25/15. 13

14 Neoadjuvant Chemotherapy Survival Benefits InternaNonal CollaboraNon of Trialists 976 panents over 6 y ( ) 3 cycles CMV vs no chemo before local treatment 428 (subset) underwent radical cystectomy 16% reducnon in risk of death with NAC at median follow- up 8 y (HR 0.84; 95% CI, , P=0.037) CMV, cisplann, methotrexate, and vinblasnne; NAC, neoadjuvant chemotherapy; HR, hazard rano; CI, confidence interval InternaNonal CollaboraNon of Trialists. J Clin Onc. 2011;29(16):

15 Neoadjuvant Chemotherapy Survival Benefits Intergroup trial SWOG Enrolled 317 panents at 126 insntunons ct2n0m0 ct4anom0 Randomized: 3 cycles neoadjuvant M- VAC, immediate radical cystectomy Primary endpoint: OS Secondary endpoint: tumor down- staging SWOG, Southwest Oncology Group; M- VAC, methotrexate, vinblasnne, doxorubicin, and cisplann; OS, overall survival Grossman HB et al. N Engl J Med. 2003;349(9):

16 Neoadjuvant Chemotherapy Survival Benefits (con7nued) Level 1 evidence from Intergroup Trial SWOG PaNents receiving NAC followed by radical cystectomy had median survival of 77 mo vs 46 mo with radical cystectomy alone Significantly more panents in NAC followed by radical cystectomy group had no residual disease (PT0) than panents in cystectomy alone group (38% vs 15%; P<0.001) Grossman HB et al. N Engl J Med. 2003;349(9):

17 Neoadjuvant Chemotherapy (NAC) in MIBC Although survival benefit seen in ennre cohort, the most improvement was in panents with >T3 Median survival from 24 vs. 65 months Grossman HB et al. N Engl J Med. 2003;349(9):859-66

18 SWOG 8710 Surgical Factors Surgical and tumor factors from 268 patients 106 surgeons, 109 institutions Multivariable analysis adjusted for MVAC/ p- stage /node status demonstrated key surgical variables Improved post-cystectomy survival: Negative margins (p=.0007) {2.7X greater risk of death M+} >/= 10 nodes removed (p=.0001) {5-year survival 61% v. 44%} Predictors of local recurrence: Positive margins (p=0001) {11X greater if M+} Fewer than 10 nodes p=0001) {6% vs. 25%} Quality of the surgery influences bladder cancer outcomes! Herr, HW et al: J Clin Oncol 22: , 2004

19 Why Aren t Eligible PaNents Receiving Neoadjuvant Chemo? In a 5- y retrospecnve analysis of 145 panents with stage T2 BC, only 17% of panents with MIBC received NAC Urologists are concerned about Determining who will benefit (risk vs benefit) Delaying cystectomy (>3 mo adverse outcomes) Toxicity from chemotherapy complicanng cystectomy (eg, renal impairment, wound healing, reduced performance status azer chemotherapy) Raj GV et al. Cancer. 2011;117(2):

20 Renal FuncNon Outcomes AZer Radical Cystectomy Most panents experience decrease in RF during long- term follow- up azer radical cystectomy Drop in RF post- op in panents with good RF pre- op supports neoadjuvant approach when feasible PostoperaNve reducnons in RF may render panents ineligible for cisplann and thus provide addinonal ranonale for use of NAC RF, renal funcnon Eisenberg MS et al. J Urol. 2014;191(3):

21 Adjuvant Chemotherapy Advantages: Administration of chemotherapy based on pathologic stage Avoids delays in potentially curative surgery avoided Disadvantages: More difficulty delivering chemotherapy in the post-operative setting

22 Adjuvant Chemotherapy: Rationale Widely used outside of clinical trials for pt3-t4 and/or N+ disease in effort to OS This approach has led to improved survival in patients with several other solid tumors Appealing to patients as well as surgeons

23 Adjuvant Chemotherapy in T3/T4 Bladder Cancer Advantages Therapy based on pathologic staging Treat primary immediately with removal of the largest and most chemo- resistant tumor burden Treat micrometastases when tumor volume low Disadvantages Unnecessary exposure to chemotherapy for those already cured with cystectomy alone Inability to evaluate the efficacy of therapy Many never receive therapy

24 Randomized Trials of Adjuvant Therapy Author Chemo Enrolled Surv Benefit Pts Richards FU/Dox pt3-4;n+ No 129 Freiha CMV pt3-4;n+ No 55 Studer Cisplatin Mostly N- No 77 Stockle MVA(E)C pt3b-4a;n+ Yes 49 Skinner CISCA pt3-4;n+ Yes 91 Paz-Ares Gem/Cis/Tax pt3-4;n+ Yes 142 All three contemporary pt2g3,pt3-4; trials closed early due to poor Cognetti Gem/Cis No 194 accrual..620 enrolled/1610 N+ planned (39%) Sternberg GC or MVAC pt3-4; N+ No 284

25 Adjuvant chemotherapy in real world patients Galsky et al. JCO 2016;34:

26 Adjuvant Chemo: Conclusions 1. Combination cisplatin-based adjuvant chemotherapy improves overall survival HR: 0.74 (95% CI, ), p= The benefit is larger in pn+ patients 3. There are limitations to this data set that likely exaggerate the treatment effect

27 NAC: Decision Making Factors that influence decision to use of NAC: Presence of lymphovascular invasion Presence of hydronephrosis Locally advanced tumor (ct3b-t4) Suspicion of lymphadenopathy on imaging Normal renal function (i.e. cisplatin) Clinical delay in presentation Good performance status

28 Clinical Staging is Inaccurate Known limitanons of staging accuracy in 70% for panents with MIBC Staging accuracy ranged from 58-80% for MRI, and 47-73% for CT scan Staging errors more common in ct2 than in ct3 4 tumors Sternberg CN, et al. Cancer 2003;97: Vargas HA, et al. Eur J Radiol, 2012;81:

29 Neoadjuvant Toxicity does not Reduce Rates of RC Despite toxicity, radical cystectomy rates are similar between groups in RCT s In SWOG- 8710, the planned cystectomy was performed in 82% of NAC and 81% of the cystectomy group Grossman HB et al. N Engl J Med. 2003;349(9): ABC Meta- analysis CollaboraNon. Lancet 2003; 361: 1927

30 Not all Pa$ents are Eligible for NAC More than 50% of panents are ineligible for cisplann because of a poor PS, impaired renal funcnon, or comorbidines In addinon, panents may not be eligible due to other factors not measured in RCT s Dash A et al. Cancer 2006;107: Witjes JA et al. Eur Urol 2014;65:778-92

31 Neoadjuvant vs Adjuvant Chemotherapy Benefits of Neoadjuvant Chemotherapy Clear evidence for efficacy from randomized clinical trials and rigorous meta- analyses Primary response as objecnve measure of treatment efficacy; ability to change treatment based on response Primary tumor response as prognosnc indicator Down- staging, improved resectability, and reduced rate of posinve margins Benefits of Adjuvant Chemotherapy Careful selecnon of panents based on precise pathological staging No delay in undergoing cystectomy AlleviaNon of panent anxiety Enhanced chemotherapeunc effect against small volume disease Early systemic treatment of possible micrometastases Exposure of loco- regional disease to chemotherapy while tumor vasculature is intact PotenNal for bladder preservanon Study of biological markers of treatment effect in surgical specimens AcceleraNon of development of new treatment regimens (able to measure tumor response rather than having to wait for panent outcomes) Black PC et al. World J Urol. 2006;24(5):

32 Neoadjuvant vs Adjuvant Chemotherapy (con7nued) Disadvantages of Neoadjuvant Chemotherapy Over- treatment in some panents If no response, delay to Nme of cystectomy may compromise outcome Disadvantages of Adjuvant Chemotherapy Poor tolerance in post- operanve period If post- cystectomy complicanons, then delay in receiving systemic treatment Efficacy measurable only with recurrence and/or survival Black PC et al. World J Urol. 2006;24(5):

33 NCCN: Which regimen and how administered? v Neoadjuvant preferred based on higher level evidence v DD-MVAC preferred over standard MVAC v Perioperative GC reasonable alternative to DD-MVAC v Carboplatin should not be substituted Dose-dense MVAC (+GCSF) x 3-4 cycles Gemcitabine plus cisplatin x 4 cycles CMV x 3 cycles

34 Optimizing perioperative chemotherapy in MIBC Disconnect between Efficacy and EffecNveness Limited Level I Evidence Poor Understanding of Disease Pathogenesis and TherapeuNc Targets

35 Efficacy versus Effectiveness Efficacy = how an intervention performs in a clinical trial population Effectiveness = how that same intervention is applied and performs in the real world

36 Use of Perioperative Chemotherapy in Bladder Cancer National Cancer Database Small increase in perioperative chemotherapy from 1998 (11.3%) to 2003 (16.8%) N = 7161 Adjuvant chemotherapy Neoadjuvant chemotherapy Surgery only Other 12% 10% 1% 77% David et al, J Urol, 2007

37 Change in POC use between NAC use increased from 10.1% to 20.8% (p=0.005), while AC use remained stable between 18.1% and 21.3% (p=0.68) Reardon ZD et al. Eur Urol 2014 PMID:

38 A large proportion of patients with urothelial cancer are cisplatin ineligible (at least one of the following) WHO or ECOG PS of 2 or Karnofsky PS of 60%- 70% CreaNnine clearance (calculated or measured) < 60 ml/min CTCAE v4 grade 2 audiometric hearing loss CTCAE v4 grade 2 peripheral neuropathy NYHA Class III heart failure Galsky et al, JCO, 2014 Galsky et al, Lancet Oncology, 2014 Dash et al, Cancer, 2006

39 Radical cystectomy recommended T2-T4a (Gr A) Do not delay >3 months or risk progression (Gr B) Lymph node dissection integral (Gr B) Laparoscopic / robotic both options (Gr C) Neoadjuvant chemotherapy should be considered and discussed Witjes JA et al. Eur Urol 2014;65:778-92

40 NAC is recommended for ct2- T4aN0M0 and should always be plannum- based (Gr A) NAC is not recommended for pts with PS >2 and or impaired renal funcnon (Gr B) In case of progression during NAC, this treatment should be disconnnued (Gr B) Witjes JA et al. Eur Urol 2014;65:778-92

41 Opportunities to improve the effectiveness of perioperative systemic therapy Decision aids/shared decision-making protocols Novel treatments that can be applied safely to a broader population of patients with bladder cancer Predictive biomarkers

42 Barriers to Progress Disconnect between Efficacy and EffecNveness Limited Level I Evidence Poor Understanding of Disease Pathogenesis and TherapeuNc Targets

43 MIBC is not a single disease Choi et al, Cancer Cell, 2014 McConkey et al, European Urol, 2014

44 Conclusions RC and extended LND is the standard to which all other therapies should be compared Cisplatin-based combination chemotherapy combined with RC and extended LND improves survival over RC alone NAC favored over adjuvant chemotherapy Surgery quality is an important predictor of survival even in patients receiving NAC

45 Conclusions The optimal chemotherapy regimen remains to be determined Patients with severely impaired RF should not receive NAC since there is no data supporting use of carboplatin in this setting Predictive biomarkers are urgently needed in order to determine which patients are more likely to benefit from chemotherapy

46 Summary Level I evidence supports cisplatin-based NAC for MIBC For patients with pt3 and/or pn+ urothelial cancer who did not receive NAC, adjuvant chemotherapy reasonable Optimize Integrative Approach(Yagoda-Vaughn) Optimizing perioperative systemic therapy will require Better informed decisions Better and safer therapies Better patient selection