Stacy Loeb, MD Department of Urology New York University (NY, USA)

Transcription

1 Practice-Changing Publications in Prostate Cancer: The Year in Review Stacy Loeb, MD Department of Urology New York University (NY, USA)

2 Acknowledgement AUA Prostate Cancer Update Course William J Catalona, MD Robert B Nadler, MD Douglas M Dahl, MD Stanley L Liauw, MD

3 Nature & Nurture

4 Genetic Factors HOXB13 (Homeobox B13)- Chromosome 17 Recent meta-analysis: 4X prostate cancer risk (including both aggressive and non-aggressive disease) Shang et al. EurUrol2013 epub. BRCA 1 & 2 Present in 0.44 and 1.2% of prostate cancers, respectively risk Gleason 8, stage T3/T4, lymph node involvement, metastases, death Castro et al. JCO 2013; 31: 1748

5 Possibly Beneficial SUNLIGHT/VITAMIN D: associated with prostate cancer risk Schwartz AnticaAg Med 2013; 13; 45 ASPIRIN: prostate cancer risk in Finland registry (OR 0.90, 95% CI ) and prostate cancer mortality after treatment in CaPSURE(HR 0.43, 95% CI ) Veitonmäkiet al. EurJ Cancer 2013, Choeet al. JCO October 2012 STATINS: Meta-analysis showed overall (RR 0.93, 95% CI , p=0.03) and significant prostate cancer (RR 0.80, 95% CI , p<0.001) Bansalet al. PLoSOne October 2012

6 Possibly Harmful DEEP FRIED FOOD: odds of prostate cancer with increased intake of deep fried foods (frenchfries, donuts, etc) Stott-Miller et al. Prostate 2013 DAIRY: prostate cancer risk in Physician s Health Study Whole milk associated with prostate cancer death Song et al. J Nutrition 2013 FISH OIL CONTROVERSY: single baseline serum level of omega fatty acids associated with prostate cancer and highgrade disease Did not assess dietary fish intake or supplements Braskyet al. JNCI 2013 epub.

7 Nature & Nurture: Take Home Messages Both genes and environment play a role in prostate cancer BRCA: associated with more aggressive disease Careful screening, not good candidates for active surveillance Eat a healthy diet, everything in moderation Aspirin and statinsmay have some benefit but also have risks USPSTF recommended against aspirin for colorectal cancer prevention due to bleeding risk

8 PSA Guidelines

9 ASCO Provisional Opinion on Screening Life expectancy >10 yr: Discuss that PSA testing may save lives but is associated with harms, including complications from unnecessary biopsy, surgery, or radiation treatment Provide information on benefits and harms written in lay language to facilitate the discussion Baschet al. JCO August 2012; 30: 3020

10 American College of Physicians GUIDANCE STATEMENT 1: Clinicians inform men aged about the limited potential benefits and substantial harms of screening Decisions to screen should be based on risk factors, a discussion of the benefits and harms, general health and life expectancy, and patient preferences GUIDANCE STATEMENT 2: Do not screen average-risk men <50y, >69y, or with a life expectancy <10-15y Qaseemet al. Ann IntMed May 2013; 158: 761

11 American Urological Association Guideline Statement 1: Recommends against PSA in men <40 yr Statement 2:Does not recommend routine screening for average-risk men ages 40-54yr Statement 3:Shared decision-making for men ages yr Weigh the benefits of preventing prostate cancer mortality in 1 man for every 1,000 men screened over a decade against the known potential harms associated with screening and treatment. Carter et al.

12 American Urological Association Guideline Statement 4:To reduce harms, a routine screening interval of 2yr may be preferred over annual screening Statement 5:Does not recommend routine PSA screening in men age 70+ years or life expectancy <10-15yr Carter et al.

13 EAU Guideline A baseline PSA should be obtained at age Use this level to determine screening intervals (~2-8y) PSA screening should be offered to men with a life expectancy 10 yr Multivariable clinical risk-prediction tools should be integrated into the decision-making process Heidenreich et al. Eur Urol 2013 epub.

14 Studies on Screening

15 Baseline PSA Predicts Metastasis & Death Nested case control study in unscreened Swedish cohort (n=21,277) Baseline PSA at predicted 25-yr risk of metastases and death Median PSA =0.7 ng/ml Highest 10 th percentile ( 1.6 ng/ml) 44% of prostate cancer deaths Vickers et al. BMJ 2013;346:f2023

16 Quality of life in European Randomized Study of Screening for Prostate Cancer Using modeling, predicted that annual screening of 1000 men would result in 73 life-years gained to 56 quality-adjusted life years taking into account downstream QOL effects (ex: impotence, incontinence) 23% of the gain in life years are potentially offset by the loss in quality of life Wide range depending on men s preferences Heijnsdijk et al. NEJM 2012; 367:

17 Shared Decision-Making 2010 National Health Interview Survey (n=3427 men ages 50-74) 55.8% ever had PSA test Examined 3 components of shared decision-making (advantages, disadvantages, uncertainty) 65% reported none, only 8% reported all 3 elements Physician-uninformed non-screening >> physician-uninformed screening Concern about non-uptake of screening withouta shared decision Han et al. Annals of Family Medicine 2013; 11: 306

18 There s More to Life Than Death USPSTF recommendation against PSA screening is largely based on assessment that harms outweigh the mortality benefit Modeling studies also focus on trading off years of life Editorial discusses that death is not the only important endpoint: dramatic reduction in metastatic disease with PSA screening Must weigh the sequellae of advanced disease (bone pain, pathologic fractures, urinary obstruction) against the side effects from treatment of early disease Hartzband& Groopman NEJM 2012; 367: 987

19 PSA Screening Reduces Metastasis Schroder et al. Eur Urol 2012; 62: Scosyrev et al Cancer 2012, 118:54 N=76,813 from European Randomized Study of Screening for Prostate Cancer (ERSPC) Intent-to-screen: 50% reduction in metastases at diagnosis, 30% reduction in metastases during 12 years follow-up Need to diagnose 12 to prevent 1 case of metastatic disease at 12yr 2008 US SEER data: compared observed cases of metastatic disease to what would be expected without screening (using pre-psa data) 8000 observed cases vs. 25,000 expected (3x higher without screening)

20 Screening: Take-Home Messages Baseline PSA in 40 s identifies high risk group Smarter screening: use level to guide screening interval Patient preferences determine the ratio of benefits and harms with screening Shared decision-making essential but underutilized There s more to life than death! Screening reduces metastatic disease

21 Biopsy & Staging

22 Prostate Biopsy Complications Systematic Review Bleeding complications: hematuria(10-84%), hematospermia(1.1-93%), rectal bleeding (1.3-45%) Mostly minor, self-limited; rarely severe/requiring hospitalization Ok to perform biopsy on aspirin Infectious hospitalizations increasing new strategies LUTS : transient dysuria in 6-25%, retention % Erectile dysfunction: controversial Loeb et al. EurUrol2013 epub

23 Should Gleason 6 Be Called Cancer? Option 1: Not Cancer Discussion about removing label of cancer to reduce anxiety and overtreatment Ex: use the term IDLE (indolent lesions of epithelial origin) for low-risk cancers Problems: Morphologically and genetically, Gleason 6 is cancer with the ability to invade tissues Biopsy Gleason score often underestimates grade and extent Option 2: Yes but rename A modernized Gleason classification ranging from 1-5 instead of 6-10 Gleason Score PrognosticGleason Grade Group Essermanet al. JAMA 2013 epubjuly 29 Carter JCO 2012; 30: What s in a name? That which we call a rose by any other name would smell as sweet 6 I/V 3+4=7 II/V 4+3=7 III/V 8 IV/V 9-10 V/V

24 ProlarisCell Cycle Progression Genes Expression of 31 cell cycle progression (CCP) genes, normalized to 15 housekeeping genes = Prolaris score (-1.3 to +4.7) CCP score sub-stratified patients with low clinical risk as defined by CAPRA-S 2 CCP score + CAPRA-S together risk stratification Potential role in active surveillance Cooperberg et al, JCO 2013

25 Reducing Inappropriate Imaging US Choosing Wisely Campaign recently identified reducing imaging of low-risk prostate cancer as a target to decrease costs and improve quality of care Since 1990, nationwide Swedish effort to reduce inappropriate imaging through presentation of guidelines and provider feedback Successfully reduced imaging for low-risk prostate cancer from 45% to 3% Makarov et al. JNCI 2013

26 Biopsy & Staging Biopsy risks increasingly recognized new strategies being explored Alternate nomenclature for low-grade disease may reduce anxiety, but more accurate staging needed New tissue tests may help improve staging

27 Treatment of Localized Disease

28 Dr. Walsh s 30-Year Outcomes 1982: Dr Walsh s 1 st nerve sparing radical prostatectomy examined his series at 30 year anniversary of this discovery N=4478 RRP from year outcomes: PFS 68%, MFS 84%, CSS 86% Anatomic RRP remains gold standard to which alternate therapies should be compared Mullins et al. J Urol 2012; 188: 2219

29 Use of Expensive Technology Jacobs et al. JAMA 2013 epub US SEER-Medicare( ) examined rates of IMRT, EBRT, robotic, open and observation Advanced technology increased from 25% to 34% for men with low-risk disease and a high risk of noncancer mortality Yu et al. JNCI 2012; 105:25. PROTONS VS. IMRT Medicare data (n=27,647) Protons had less GU toxicity at 6 months but no difference in GU or GI toxicity by 12 months Cost : Protons $32,428 versus IMRT $18,575

30 15-year Functional Outcomes After Treatment Prostate Cancer Outcomes Study: n=1655 men treated in Prospensity score adjustment Continued decline in both groups Early differences minimized by 15y No control group RP 5/15 y RT 5/15 y Incontinence 13/18 5/9 Bowel urgency Poor erections Symptoms over time 16/22 31/36 76/87 72/94 Resnick et al. NEJM 368:436, 2013

31 Active Surveillance Outcomes Bulet al. EurUrol2012 epub PRIAS: n=2494 on AS Median f/u 1.6 years Estimated 4-year therapy-free survival= cases of metastatic disease, 0 deaths Xia et al. ClinCancer Res 2012; 18:5471 Model of CaPSUREand Johns Hopkinsto estimatedifference in immediate surgery versus active surveillance 2/3 will eventually need treatment (at average of 6.4 yr) No significant difference in overall survival

32 Phase 1 Trial of Focal Laser Therapy N=9 patients with a focal suspicious lesion on MRI in same location as positive biopsy Patient in MRI machine laser target lesion via brachytherapy template hours OR time, no immediate complications Mean PSA 5.5 before treatment, also 5.5 at 6mos postop(p=0.8) 3 patients with 5 point decrease in SHIM at 6 mos 2/9 patients had Gleason 6 cancer on biopsy at 6 mos Oto et al. Radiology 2013 epub.

33 Localized: Take-Home Messages Open prostatectomy excellent long-term oncologic outcomes Increased use of expensive treatment alternatives Active surveillance safe in short-term Focal therapy modalities expanding Need more data on cost-effectiveness

34 Recurrent & Advanced Disease

35 Long term update of EORTC 22911: Adjuvant RT Phase III study of men with pt3 or positive margins, given RT vs observation (n=1005) Median f/u 10.6 yr: improvement in biochemical progression-free survival (61% vs. 41%) No difference in overall survival, unlike SWOG Bolla et al. Lancet 380:93, 2012

36 Intermittent vs Continuous Androgen Deprivation 765 continuous vs. 770 intermittent androgen deprivation Median survival = 5.8y continuous vs. 5.1y intermittent Hazard ratio for death with intermittent therapy, 1.10; 90% CI 0.99 to 1.23) Cannot rule out a 20% greater risk of death with intermittent therapy than with continuous therapy Intermittent therapy was associated with better erectile function and mental health at month 3 but not thereafter Hussainet al. N Engl J Med 2013; 368: 1314.

37 First-Line Abiraterone N=1088 with mcrpc(no prior chemo) Abiraterone+ prednisone improved median progression free survival of 16.5 vs. 8.3 mo (HR 0.53 p<0.001), delayed time to pain and chemo Improved OS (HR 0.75 p<0.01) endpoint not reached at cessation of study FDA approved for pre- and post-chemo use Ryan et al. NEJM 2013; 368:138-48

38 AFFIRM: Enzalutamide(MDV 3100) Does not require prednisone Phase 3 trial N=1199 with metastatic castrateresistant prostate cancer Study stopped because of prolonged survival Time to progression: 8.3 vs 2.9 months Time to skeletal event: 16.7 vs 13.3 months Side effects: fatigue, diarrhea, 0.6% seizures Scher et al for AFFIRM. NEJM 2012; 367:1187

39 Radium-223 (Alpharadin) First ever radiopharmaceutical Bone metastasis-targeting agent (binds to areas of increased bone turnover and emits high energy alpha particles of short-range) ALSYMPCA trial: Radium-223 vs. placebo injection for bone metastatic CRPC Improved overall survival (median 14.9 vs mos) Reduced skeletal-related events, improved QOL Minimal myelotoxicity, few adverse events Parker et al. NEJM 2013; 369: 213

40 Advanced Disease: Take Home Message Conflicting data on benefit of adjuvant radiation after prostatectomy Consider early salvage strategy Intermittent ADT not non-inferior Explosion of new drugs for CRPC Timely given projected resurgence of metastatic disease with less screening