Prostate Cancer Active Surveillance: Rationale, Outcomes and Future Directions

Transcription

1 Prostate Cancer Active Surveillance: Rationale, Outcomes and Future Directions Daniel W. Lin, MD Professor and Chief of Urologic Oncology Bridges Endowed Professorship of Prostate Cancer Research Department of Urology, University of Washington State of Ac*ve Surveillance 1

2 Important AS Questions 1. How have the patient population and the natural history of prostate cancer changed in the last 20 yrs? 2. How are active surveillance and other observational strategies defined? 3. What are the patient-experienced comparative short- and long-term health outcomes of active surveillance for localized prostate cancer? 4. What factors affect the offer of, acceptance of, and adherence to active surveillance? 5. What are the research needs regarding active surveillance in localized prostate cancer? Background and Rationale Burden of prostate cancer in 2012* 241,740 new cases 28,170 deaths Stage migration of disease Primarily due to PSA screening Low risk disease predominates Number of diagnosed outweighs lethal cases (overdetection) Majority of men with newly diagnosed prostate cancer (even low risk) treated with primary curative therapy (overtreatment) Side effects of primary curative treatment *Siegel et al, CA Cancer J Clin,

3 PSA Screening Practices Drazer et al, JCO 29: , 2011 The Changing Face of Prostate Cancer Cooperberg et al. J Urol 2007; 178:S14 3

4 Heterogeneous Natural History Esserman et al. JAMA 2009; 302:1685 Overtreatment vs. Undertreatment Cooperberg et al. J Clin Oncol 2010; 28:1117 4

5 Contemporary 10-yr Survival in Gleason 5-7! Lu-Yao et al, JAMA 302:1202-9, 2009 Risk of PCa Death after RP Risk Group Pts PCa Death 15- yr PCSM High 1,962 (17%) 121 (61%) 19% Intermediate 4184 (37%) 64 (32%) 10% Low 5200 (46%) 14 (7%) 2% Stevenson et al, JCO 27: 4300,

6 695 men randomized to RP (347) or WW (348) Localized disease, PSA < 50, well- or moderatelydifferentiated Median f/u 8.2 years N Engl J Med 352: , 2005 Cancer Control: RP vs. WW (Bill-Axelson et al,nejm 2005) Risk of distant metastases: WW = 22.7%, RP = 14.4% Relative Risk = 0.60 ( ) Disease-specific mortality: WW = 14.4%, RP = 8.6% Relative Risk = 0.56 ( ) Overall mortality: WW = 30.5%, RP = 23.9% Relative Risk = 0.74 ( ) 6

7 Prostate Cancer Mortality: Radical Prostatectomy vs. Watchful Waiting Bill-Axelson, Holmberg, et al, NEJM 2005 Cancer Control: RP vs. WW (Bill-Axelson et al, NEJM 2005) Caveats: Not representative of patients seen in USA 75% of patients with palpable cancer <15% detected by PSA >45% with PSA > 10 Majority of benefit in < 65 yo 7

8 PIVOT Results (Wilt et al, NEJM 2012) Prostate Intervention Versus Observation Trial (PIVOT). 731 patients randomized to RP or WW > 50% with nonpalpable disease Preliminary results: (Overall survival) All patients: HR 0.88 ( ), p=0.22 Low risk: HR 1.15 ( ), p=0.45 Intermediate risk: HR 0.69 ( ), p=0.04 PSA <10: HR 1.03 ( ), p=0.82 PSA >10: HR 0.67 ( ), p=0.02 Wilt et al, NEJM

9 Challenge in managing localized CaP Natural history Men who could avoid therapy (or avoid diagnosis)! Men who benefit from treatment! Men who die despite radical treatment! Bill-Axelson, Holmberg, et al, NEJM 2005 PLCO: mortality ESPRC: mortality, ~1 death per 1000 screened Overdiagnosis 50% of screen-detected cases 48 men additional diagnosed for every death prevented Morbidity from biopsy (ProtecT trial, UK) Serious infections /urine retention in 0.5% to 1% of biopsies Harms of treatment (SPCG-4, CaPSURE, PCOS, etc) RP 0.5% perioperative death, 0.6% - 3% CV events RP 33% ED, 20% incontinence RT 14% ED, bowel dysfunction 9

10 Important AS Questions 1. How have the patient population and the natural history of prostate cancer changed in the last 20 yrs? 2. How are active surveillance and other observational strategies defined? 3. What are the patient-experienced comparative short- and long-term health outcomes of active surveillance for localized prostate cancer? 4. What factors affect the offer of, acceptance of, and adherence to active surveillance? 5. What are the research needs regarding active surveillance in localized prostate cancer? Treatment Options in Localized Prostate Cancer 1. Surgery robotic/laparoscopic or open 2. Radiation Therapy - Seeds - External Beam - Combination seeds and external beam 3. Hormonal Therapy (alone or in combination) 4. Watchful Waiting 5. Ablative therapy (cryo, HIFU) 10

11 Prostate Cancer Management " Semantics:" " Watchful Waiting" Active Surveillance" Expectant Management" Active Surveillance 11

12 Active Surveillance vs. Watchful Waiting" Active Surveillance Watchful Waiting Aim Individualize treatment Avoid treatment Patient Characteristics Tumor characteristics Monitoring Indications for Treatment Fit for radical treatment Low-risk Frequent PSA Repeat biopsy Increase in PSA Increase in grade/volume Age > 75, Life expectancy < 10 years Any PSA optional/unimportant No repeat biopsy Symptomatic progression Treatment timing Early Delayed Treatment intent Radical Palliative Adapted from Parker, Lancet Oncology, 2004 Watchful Waiting: Cancer-Specific and Overall Mortality Treatment Trends in Low Risk Prostate Cancer Alive, % Years following diagnosis Albertsen et al, JAMA 2005;293: Cooperberg et al, JCO 2010;28:

13 Prostate Cancer Classification" Low risk (D Amico, NCCN, AUA)" " Stage " T1c/T2a" " PSA <10 ng/ml" " Gleason score" 6" " Very low risk (Epstein):" " Stage T1c" " PSAD < 0.15" " Gleason score" 6" " < 3 cores with " cancer" 50% " of any core involved" " Active Surveillance Entry Criteria" Royal Marsden (n=326) Clin Stage PSA Gleason Bx info Other T2a 15 7 (3+4) 50% cores Univ of Miami (n=230) T cores, 20% of any core Johns Hopkins (n=633) T1c NR 6 2 cores, 50% of any core PSAD 0.15 UCSF (n=376) T % cores, 50% of any core Univ of Toronto (n=453) NR 10/15 6 / 7 (3+4) NR MSKCC (n=238) T2a cores, 50% of any core ESPRC (n=616) T cores PSAD

14 Active Surveillance Monitoring Plan" Royal Marsden (n=326) PSA/DRE PSA: q mo x 1 yr, q 3 x 1 yr, then q 6 mo DRE: q 3 mo x 2 yrs, then q 6 mo Repeat Bx at mo, then q 2 yr Univ of Miami (n=230) q 3-4 x 2 yr, then q 6 mo at 9-12 mo, then q 12 mo Johns Hopkins (n=633) UCSF (n=376) Univ of Toronto (n=453) MSKCC (n=238) ESPRC (n=616) q 6 mo q 3 mo q 3 mo x 2 yr, then q 6 mo q 6 mo PSA: q 3mo x 2 yr, then q 6 mo DRE: q 6 mo x 2 yr, then q 12 mo q 12 mo q mo at 6-12 mo, then q 3-4 yr at mo, then q 2-3 yr at 1, 4, 7, and 10 yr Active Surveillance Progression Definitions Biopsy Information Increase in tumor grade Increase in amount of cancer on biopsy PSA Doubling time or velocity Stage Digital rectal examination findings 14

15 AS: Progression Definitions" PSA Gleason Bx info Other Royal Marsden (n=326) PSAV > 1 ng/ml/yr 1º grade 4 > 50% of cores Univ of Miami (n=230) NR Any pattern 4 "any increase" Johns Hopkins (n=633) UCSF (n=376) none Any pattern 4 PSADT and/or PSAV Any pattern 4 >2 cores, >50% of any core NR Univ of Toronto (n=453) PSADT < 3 yrs Any increase NR DRE change MSKCC (n=238) PSA > 10 Any pattern 4 >3 cores, >50% of any core DRE change ESPRC (n=616) PSADT < 3 yrs Any pattern 4 >2 cores >ct2 Progression Definition Issues PSA Multiple studies report PSA kinetics not related to progression or pathology Increase Grade Interobserver variability in pathology evaluation Increase in volume Lack of standardization of biopsy technique McKenney et al, J Urol 186: 465-9,

16 Pathology Issues Digital image review of prostate biopsies 11 GU pathologists from 7 institutions N = 97 consecutive patients on AS Interobserver reproducibility: Classic Gleason patterns = kappa 0.76 Tangential glands/small foci = kappa % of biopsies with at least 1 focus of tangential section issue. McKenney et al, J Urol 186: 465-9, 2011 Cancer Volume Definition Issues Variable definitions for entry and progression Absolute number of cores versus proportion of cores 2 cores at JHU vs. 33% of cores at UCSF Estimated vs. calculated percentage core involvement Impact of biopsy methodology Saturation biopsy Linear extent versus percentage involvement Clinically insignificant tumor nomograms Contemporary definition: threshold volume for Gleason 6 disease could be 1.3cc* *Wolters et al, J Urol 185: 121-5,

17 PSA Progression = Unreliable endpoint Ross et al, J Clin Onc 28: , 2010 (Hopkins) Neither PSADT or PSAV predictive of biopsy progression or adverse pathology on RP Loblaw et al, J Urol, 184: , 2010 (Toronto) Threshold trigger: 14% to 42% recommended for tx PSADT: 37% to 50% PSAV: 42% to 84% AS: Progression/Treatment Rates" Progression-Free Rate Predictors Treatment Notes Royal Marsden (n=326) 73% f/t PSA and T stage Near equal grade and volume, 8% no progression Univ of Miami (n=230) 86% Tumor on first serial biopsy Grade and volume only Johns Hopkins (n=633) 81% at 2 yr 59% at 5 yr i PSAD 38% grade, 36% volume, 26% no progression UCSF (n=376) 85% at 2 yr 65% at 5 yr ipsad 67% grade or volume, 33% no progression Univ of Toronto (n=453) MSKCC (n=238) ESPRC (n=616) 70% T stage and Gleason 80% at 2 yr, 60% at 5 yr (including PSA) 91% at 2 yr, 76% at 5 yr (excluding PSA) 78% at 2 yr 62% at 5 yr Tumor on first serial biopsy NR 48% PSA, 27% grade, 10% no progression, 15% other NR NR 17

18 Is Treatment after AS = Immediate Treatment? Cooperberg et al (UCSF), J Clin Onc 29: , 2010 Is Treatment after AS = Immediate Treatment? Ross et al (J Clin Onc 28: , 2010) and Tosoian et al, (J Clin Onc 29: , 2011) (Hopkins) n=192 treated patients (96 radiation, 96 surgery) Surgery: 62% favorable, 32% unfavorable pathology 9.4% biochemical recurrence Klotz et al, J Clin Onc 28: , 2009 (Toronto) n=125 treated patients (90 radiation, 35 surgery) 50.4% biochemical recurrence (13% of total cohort) 18

19 Active Surveillance - Worldwide Summary of Studies Cooperberg, Carroll, Klotz. J Clin Oncol 29: , 2011 Men with New Diagnosis of Prostate Cancer = Not AS candidate = Classic AS candidate 19

20 Men with New Diagnosis of Prostate Cancer > 90% receive treatment (surgery or radiation) Not AS candidate Classic AS candidate, No progression (3 yr follow-up) = = = AS candidate, Progression on AS (3-yr follow-up) Important AS Questions 1. How have the patient population and the natural history of prostate cancer changed in the last 20 yrs? 2. How are active surveillance and other observational strategies defined? 3. What are the patient-experienced comparative short- and long-term health outcomes of active surveillance for localized prostate cancer? 4. What factors affect the offer of, acceptance of, and adherence to active surveillance? 5. What are the research needs regarding active surveillance in localized prostate cancer? 20

21 You are perfect for active surveillance I am here for robotic prostatectomy You have very low risk disease I am here for robotic prostatectomy We have a protocol for you that is safe How can I be sure? Please take out my prostate The protocol is called Canary PASS My wife says that my prostate belongs in the trash can I am going to Vancouver to see Dr. Gleave. 21

22 Factors Affecting Practice of Active Surveillance Physician Factors Fear of losing window of curability Lack of long-term data to support use Inconsistent study designs Litigious health care system (in US) Potential incentives favoring treatment over AS Patient Factors Fear of losing window of curability Fear of side effects of primary therapy vs. complications of biopsy Race/ethnicity/family history Lack of decision-making support tools Cost Cost Analysis of Active Surveillance Multiple studies report decreased costs with AS vs. other primary treatment modalities Keegan et al, Cancer, in press, 2012 Corcoran et al, Urology, 2011 Eldefrawy et al, Urol Onc,

23 Cost Analysis of Active Surveillance Costs highly dependent on frequency of serial biopsies Duration of active surveillance inversely related to cost savings Costs of primary curative treatments (RP, EBRT, brachy) include hospital, pathology, anesthesia, etc Ø Urologist reimbursement substantial for serial office visits, biopsies, etc* Most analyses do not include costs associated with management of treatment-related complications and adjuvant/salvage therapies *Manoharan et al, Prostate Cancer Prostate Diseases, 2010 NCI: Summary of Research Needs Improve pathologic, molecular, genetic and image predictive markers Examine impact of socioeconomic status, race/ethnicity Determine optimal candidates and follow-up protocols (e.g. who might need inactive surveillance?) Enhance the decision-making process and communication Study lifestyle and therapeutic interventions Create registry-based cohort studies 23

24 PASS Sites University of British Columbia (Martin Gleave) University of Washington and DMCC Seattle VA Hospital (Dan Lin) Fred Hutchinson Cancer Center (Ziding Feng) University of California, San Francisco (Peter Carroll) Stanford University (Jim Brooks) University of Michigan (John Wei) Beth Israel Deaconess Medical Center (Marty Sanda) Eastern Virginia Medical School (Ray Lance) University of Texas, San Antonio (Ian Thompson) Clinically localized prostate cancer No previous cancer treatment Canary PASS Protocol Patient consultation STUDY ENTRY Active Surveillance Serial exam/psa, prostate biopsy Continued Active Surveillance Progression (PSA, Histology, Clinical) Recommended Primary Treatment Tissue, serum, plasma, DNA, urine, EPS 24

25 Goals of PASS Establish the first multi-site active surveillance cohort in North America. Study natural history of low risk prostate cancer in systematic fashion. Assemble a repository of high quality biospecimens suitable for biomarker discovery and validation. Test biomarkers to distinguish lethal and benign prostate cancer. PASS eligibility criteria The study is enrolling participants who meet the following criteria: Histologically-confirmed adenocarcinoma of the prostate. Elected Active Surveillance as a management plan for prostate cancer. Clinically localized prostate cancer: T1-2, NX or N0, MX or M0. No previous treatment for prostate cancer, including hormonal therapy, radiation therapy, surgery, chemotherapy. ECOG Performance Status 0 or 1. Recent prostate biopsy. Willingness to undergo serial prostate biopsy. No history of other malignancies. Ø Broad criteria beneficial for biomarker studies Ø Can parse cohort for study specific eligibility criteria 25

26 Evaluation and Specimen Collection PSA q 3 mo DRE q 6 mo TRUS and Prostate Biopsy Ø At 6-12 mo from diagnosis, at 24 mo, then q 2 yr Research Specimens Ø Blood and urine q 6 mo Ø Tissue at each biopsy Ø DNA at study entry Biospecimen Resource: PASS Specimens Blood Urine Original Specimens Red (serum) Purple (plasma) BC (buffy coat) Baseline only First yellow Second yellow Baseline only Urine Child Specimens 20 serum 2 white blood cells 20 plasma 2 DNA 2 whole urine 2 urine sediment 2 urine supernatant At time of biopsy or RP, collect FFPE and OCT embedded prostate tissue 26

27 Canary Prostate Active Surveillance Study (PASS) Data and bio-specimens collected at clinical sites Stanford* UCSF* UBC* UW* UTHSCSA* VAPSHCS* BIDMC UM EVMS De-identified clinical data and data from assays to DMCC Data Management and Coordinating Center Data repository, statistical center, coordinating center Central Biospecimen Repository Blood and urine specimens; prostate tissue may remain at sites Specimens to Central Biospecimen Repository for storage and distribution Assay data to DMCC for analysis Third party not-for profit study site Collaborating assay site for study Consortium** Assay site for study * Original site **Any of the sites listed above Committees Executive Biomarker review Publications PASS Infrastructure Conference schedule Monthly conference calls Bi-annual face-to-face meetings Data and specimen management oversight Site visits Quality control reporting Central repository for biospecimens PASS Consortium Collaboration Agreement executed at participating sites 27

28 Demographics (baseline) N = 831 on 1/15/13 Age at study entry PSA Gleason Score Mean 63 Mean (92) <50 30 (4) (41) 7 (3+4) 65 (8) (28) (52) 7 (4+3) 3 (<1) (53) > (7) > (15) Clinical T-stage % Cores with cancer T1a/b 7 (1) 10% 400 (58) T1c 624 (86) 11-33% 281 (39) T2a 85 (12) 34% 23 (3) T2b/c 7 (1) Race: 90% Caucasian, 6% African American, 3% Asian, 1% American Indian/Alaska Native Ethnicity: 3% Hispanic Progression Events n = 831 Progression Type Number of Participants (%) Any Grade Any Volume Any Clinical Grade Only 104 (54) Volume Only 26 (14) Clinical Only 16 (8) Grade and Clinical 9 (5) 9-9 Grade and Volume 28 (15) Grade, Volume, Clinical 8 (4) Total

29 Treatment N = 831 Treatment with study defined progression? Grade Volume Clinical Yes 93 No 43 Total 136 ~16% of current cohort has been treated One third have received treatment without study defined progression Treatment type: 93 surgery, 41 radiation, 1 cryotherapy, 1 hormone therapy Ancillary Studies PCA3 and T2:ERG in urine Do urine markers correlate with baseline disease characteristics? PSA kinetic methodology Does frequency of PSA assessment (q 3 mo vs q 6 mo) affect PSADT calculations? Correlation with progression Does negative PSAV correlate with no evidence of progression on AS? 29

30 Marker Correlation with Clinical/pathologic Variables (n=387) Serum PSA Prostate volume Gleason score (entry biopsy) Tumor volume (% positive cores) Variable r s p-value* T2:ERG score PCA3 score T2:ERG score PCA3 score PSA (serum) 0.39 < T2:ERG score PCA3 score T2:ERG score 0.30 <0.001 PCA3 score Ø No significant correlation with Race, Clinical Stage, Family History, AUASS, time of PCa dx, PSADT, BMI, Time from biopsy to urine collection, medication use Lin et al, Clin Canc Res, in press, 2013 PSA kinetics at 3 vs. 6 month intervals PSADT (3 mos) No Progression (PSADT>3 yrs) PSADT ( 6 mos) No Progression Progression (declining PSADT) (PSADT<3 yrs) Total No Progression (PSADT>3 yrs) No Progression (declining PSADT) Progression (PSADT<3 yrs)

31 PSA kinetics at 3 vs. 6 month intervals PSA kinetics at 3 vs. 6 month intervals 31

32 PSA Kinetics and Progression on AS 0.5 PSA Velocity (ng/ml/yr) No Progression Progression Ross et al, J Clin Onc 28: , 2010 PSAV threshold Sensitivity Specificity NPV PPV (ng/ml/yr)

33 Ongoing Work Longitudinal urine biomarker changes Variability of markers Correlation to progression Modeling intensity of surveillance Need for surveillance biopsy based on PSA kinetics and other clinical factors Predictor of negative biopsy Testing established platforms for association to progression Progression Biomarkers Germline DNA: risk polymorphisms Blood: PSA and derivatives methylated/mutated DNA micrornas antibody signatures Tissue (Cancer/Benign) Transcript/Protein signatures DNA (CNV) Field Effect Urine: PCA3 methylated DNA Metabolites gene rearrangements Imaging: Ultrasound MRI (multiparametric) PET Targeted: antibody-based (PSCA,VE 33

34 Provocative Questions Is intensive surveillance needed? Inactive Surveillance Role of prevention strategies? Diet and lifestyle 5ARI, Targeted AR agents SWOG Role of imaging and focal therapy? Impact on quality of life? Methods to assist patient decision-making? Predic*ng Insignificant Cancer Shukla-Dave et al. BJU Int 2007; 99:786 34

35 Men with New Diagnosis of Prostate Cancer > 90% receive treatment (surgery or radiation) Not AS candidate Classic AS candidate, No progression (3 yr follow-up) = = = AS candidate, Progression on AS (3-yr follow-up) Impact of Biomarkers on Prostate Cancer ~50-60% receive treatment (surgery or radiation) + = Primary Treatment (Surgery or Radiation) = Active Surveillance 35

36 Strategy (outcome- predicgve markers) Indolent forever Indolent now could progress Steady state PotenGally Lethal Don t worry, be happy ü Progression prevengon ü Re- evaluate (AS) Change of state Treat for Cure 36

37 Candidates Very low risk with < 20 yr life expectancy Low risk with <10 yr life expectancy Monitoring PSA: at least q 6 mo, DRE: q 12 mo Biopsy: within 18 mo (unless <10 core initial bx), as often as q 12 mo, not indicated if >75 yo or <10 yr life expectancy PSA kinetics may not be reliable Men with low-risk localized prostate cancer who are considered suitable for radical treatment should first be offered active surveillance. Recommended in: stage T1c, Gleason 3+3, PSAD < 0.15, and <50% of total cores, < 10 mm of any core involved Active surveillance should be discussed as an option with men who have intermediate-risk localized prostate cancer 37

38 Active Surveillance Paradigm Immediate Treatment Active Surveillance Cure Care War Peace Survivor Participant Schellhammer, MD: NCI State-of-the-Science AS Conference, Bethesda, MD, December 2011 Take Home Points Better able to identify low risk disease Overtreatment of low risk prostate cancer Randomized trials support active surveillance (in select populations) Active surveillance appears safe Recommended by major medical guideline panels Patients with classic low risk disease appear ideal candidates Program of serial exams and biopsies accepted Critical needs: new biomarkers and collaborative efforts 38

39 PASS Team (partial list) FHCRC Pete Nelson Ziding Feng Elissa Brown UBC Martin Gleave Larry Goldenberg Ladan Fazli Alan So EVMS Raymond Lance Dean Troyer Stanford Jim Brooks Jesse McKenney UCSF Peter Carroll Matt Cooperberg Max Meng Jeff Simko BIDMC Martin Sanda U. Michigan John Wei Priya Kunju UTHSCSA Ian Thompson Marlo Nicolas U. Washington Bill Ellis Lisa Newcomb Larry True Canary Foundation Heidi Auman Sarah Hawley Don Listwin Early Detection Research Network/NCI Gen-Probe, Inc Jack Groskopf 39

40 Pathologic findings at Prostatectomy, N = 91 Biopsy Prostatectomy Gleason 34% pos Gleason N cores TOTAL no yes unknown Positive margins Extraprostatic extension Seminal vesicle invasion Node positive *38 report 0 lymph nodes removed 40