Edward P. Gelmann, MD

Transcription

1 Prostate Cancer Edward P. Gelmann, MD

2 Prostate Cancer Etiology and Ep pidemiology Screening Pathology Staging Localized Disease Metastatic Disease

3 normal prostate epithelium GSTP1 CpG island hypermethylation RNASEL, MSR1, or other germline mutation prostatic intraepithelial neoplasia ETS Translocation (AR R-Dependent) P27 decrease in NKX3.1 localized prostate cancer AR DNA damage Survival signal metastatic prostate cancer PTEN, P53, RB, MYC castration resistant cancer

4 Prostate Cancer

5 Prostate Cancer SEER

6 Prostate Cancer SEER

7 Prostate Cancer

8 Prostate Cancer JNCI 95:1357, 2003

9 Prostate Cancer Epidemiology and Etiology Screening Pathology Staging Localized Disease Metastatic Disease

10 Epithelial Cells PSA

11 PSA Serine protease Indicator of cancer activity post treatment Screening tool

12 PSA Refinements: PSA Density Free/Total PSA PSA Velocity

13 Reasons to Initiate Mass Screening for Cancer 1. The disease should represent a substantial public health burden and have a prevalent, asymptomatic premetastatic phase. There are >200,000 new cases of prostate cancer/year. Early stage prostate cancer is curable.

14 Reasons to Initiate Masss Screening for Cancer 2. The asymptomatic premetastatic phase should be recognizable. Early stage prostate cancer can be detected using DRE and PSA.

15 Reasons to Initiate Masss Screening for Cancer 3. A good screening test that has reasonable predictive value, low cost and is acceptable to screener and subject. For a man >50, positive pred dictive value of a PSA > 4.0 is 20-30%, and PSA > 10, 42-64%. PSA detection rate is 3%. PSA costs $25-60.

16 Reasons to Initiate Masss Screening for Cancer 4. Curative potential should be better in early than in late state disease. 10-Yr progression-free survival with: organ-confined disease - 69% with regional extension %, with distant metastases - 15%.

17 Reasons to Initiate Masss Screening for Cancer 5. Screening should improve outcome as measured by cause-specific mortality. Randomized trial data do not yet support the use of screening for prostate cancer.

18 Prostate Cancer Screening Andriole NEJM 360:1310, 2009

19 Prostate Cancer Screening Andriole NEJM 360:1310, 2009

20 Prostate Cancer Screening Schroder NEJM 360:1320, 2009

21 Prostate Cancer Screening Schroder NEJM 360:1320, 2009

22 Prostate Cancer Epidemiology and Etiology Screening Pathology Staging Localized Disease Metastatic Disease

23 Prostate Histology - Gleason Grading

24 Prostate Histology - Gleason Grading

25 Localized Prostate Ca ancer Natural History lbertsen JAMA 293: 2095, 2005

26 Prostate Pathology

27 Prostate Cancer Epidemiology and Etiology Screening Pathology Staging Localized Disease Metastatic Disease Other Considerations in Management

28 Prostate -TUR

29 Staging AJCC 6 th th Ed dition T1 -Incidental histologic finding a - <5% of tissue b ->5% of tissue c - PSA detection T2 -Clinically ypresent limited to prostate a ½ lobe b - > ½ of one lobe c both lobes T3 - Invades beyond apex, capsule, bladder neck or SV, but not fixed a ECE b - SV T4 Fixed or invades other structures or fixed

30 Staging AJCC 6 th th Ed dition Nodal status N0 - no nodes involved N1 regional nodes Metastases M0 M1a distant nodes M1b bone M1c other sites w/ or w/o bone

31 Prostate Cancer Epidemiology and Etiology Screening Pathology Staging Localized Disease Metastatic Disease

32 Pelvic Anatomy

33 Trends in Treatment of Prima ary Prostate Cancer CaPSURE Cooperberg JNCI 95:981, 2003

34 Treatment

35 Lead-Time Bias Screen Detection Symptoms Lead Death Time Bias

36 Survival after Prostat te Cancer Diagnosis Lu-Yao JAMA 302:1202, 2009

37 Treatment of Local Pr rostate Cancer Radical Retropubic Prostatectomy

38 Treatment of Local Pr rostate Cancer Radical Retropubic Prostatectomy

39 Treatment of Local Pr rostate Cancer Radical Retropubic Prostatectomy

40 Treatment of Local Pr rostate Cancer Radical Retropubic Prostatectomy

41 Prostate RRP Surviv val Zhang Cancer 100:300, 2004

42 Prostate Cancer Disease Extent and Survival

43 Prostatectomy v. Watchf ful Waiting Bill-Axelson JNCI 100:1144, 2008

44 Prostatectomy v. Watchf ful Waiting Bill-Axelson JNCI 100:1144, 2008

45 Progressive Disease PSA after RRP should < 0.01ng/ml 01 Two successive = recurrence Salvage XRT

46 Treatment of Local Pr ostate Cancer Morbidity of RRP Begg NEJM 346:1138, 2002

47 Treatment of Local Pro ostate Cancer Morbidity of RRP Begg NEJM 346:1138, 2002

48 Treatment of Local Pr rostate Cancer Conformal RT

49 Treatment of Local Pr rostate Cancer Conformal RT

50 Treatment of Local Pr rostate Cancer Conformal RT

51 Treatment of Local Pr rostate Cancer IMRT One of several strategies to improve risk benefit ratio Need to worry about potential downside If imaging g (MR) can identify regions of more cancer, IMRT can tailor the dose accordingly

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53 Treatment of Local Pr rostate Cancer Brachytherapy

54 Treatment of Localize ed Prostate Cancer Acute Morbidity Potosky et al JNCI 92:1582, 2000

55 Treatment of Localize ed Prostate Cancer Late Morbidity Gore JNCI 101:888, 2009

56 Treatment of Localize ed Prostate Cancer Morbidity at 2 yr prostatectomy radiotherapy incontinence 96% 9.6% 35% 3.5% impotence 79.6% 61.5% Potosky et al JNCI 92:1582, 2000

57 Prostate Cancer Epidemiology and Etiology Screening Pathology Staging Localized Disease (Locally Advanced) Metastatic Disease

58 Endocrine Axis in Prostate Cancer GnRH agonist Adrenal Blockade Orchiectomy Antiandrogens Finasteride

59 Neoadjuvant Therapy Surgery Diminish the size of large cancers Four Randomized trials - increased rate of negative margins There was no effect on lymph node emetastases No effect on DFS

60 Neoadjuvant Therapy Irradiation for Stage C RT + Goserelin (3 yr) v. RT followed by appropriate Rx Bolla et al,nejm 337: , 1997

61 Neoadjuvant Therapy Stage C Bolla Lancet 360:103, 2003

62 Neoadjuvant Therapy Stage C Bolla Lancet 360:103, 2003

63 Prostate Cancer RT + HT: OS Bria Cancer 115:

64 Prostate Cancer Epidemiology and Etiology Screening Pathology Staging Localized Disease Metastatic Disease

65 Hormonal Therapy Progressive Disease Metastatic Diseasee

66 Progressive Disease Early v. delayed androgen ablation Benefits of cancer control vs. morbidity of androgen ablation

67 Progressive Disease Morbidity of androge en ablation Bone mineral density Fatigue Diabetes mellitus Cardiovascular risk

68 Early Androgen Ablat tion Rx N= Surgery 51 Surgery + 47 AA 7 yr Survival 65% 85% p=0.001 Messing et al,nejm 341:1781-8, 1999

69 Total Androgen Ablat tion Adrenal androgens 5-10% circulating androgens

70 Hormonal Therapy Metastatic CaP nilutamide flutamide CPA Lancet 355:1491, 2000

71 Androgen Ablation Lu-Yao JAMA 300:173, 2008

72 Androgen Ablation Lu-Yao JAMA 300:173, 2008

73 Progressive Metastatic Prostate Cancer Androgen ablation should not be discontinued Even after progression on a GnRH agonist AR expression per rsists

74 AR Structure DNA-binding

75 Activation of Transcription

76 Androgen-Independent Androgen receptor gene amplification Prostate Cancer AR mutations AR phosphorylation AR coactivator over expression Increased expression of androgen synthetic enzymes Alternate splicing to generat te ligand-independence independence

77 Second-Line Hormona al Rx AAW Ketoconazole Adrenal Blockade Steroids Aminoglutethimide

78 Progressive Prostate Management Cancer Bone mets - location prophylaxis Pain management Second-line hormonal Rx Chemotherapy

79 CRPC Petrylack NEJM 351:1513, 2004

80 CRPC Petrylack NEJM 351:1513, 2004

81 Summary Screening is common and problem than a solution may be more of a We are unable to identify cancers that need treatment Local therapy still has significant morbidity Systemic therapy carries risks and benefits Better targeting of the AR may be beneficial