Prostate Cancer. To screen or not to screen, that is the question

Transcription

1 Prostate Cancer To screen or not to screen, that is the question Michael D Marcus, M.D. Assistant Professor of Urology St Louis University Chairman, Department of Surgery SSMHealth St Mary s Hospital, St Louis, Missouri

2 Outline History of Prostate cancer screening Prostate Specific Antigen Trans Rectal Biopsy Prostate Cancer Staging European Randomized Screening for Prostate Cancer Trial Prostate, Colon, Lung, Ovarian Cancer Trial United States Preventive Services Task Force Current American Urological Association Guidelines

3 Outline (continued) Additional Testing: Free PSA Select MDx PSA Density Confirmed MDx PSA Velocity Oncotype Dx Prostate Health Index Decipher 4K Score Prolaris PCA3 MRI / US Fusion

4 History (19 th Century) Prostate Cancer was universally fatal Early stage prostate cancer asymptomatic Widespread metastases at the time of initial presentation: Severe bone pain Obstructive uropathy Uremia Urinary tract infection Weight loss Debility

5 History (1904) Hugh Hampton Young, M.D. Chairman, Division of Urology, Johns Hopkins Hospital Pioneered Radical perineal prostatectomy Promoted the use of the digital rectal examination for prostate cancer screening

6 Digital Rectal Examination As a screening test for early stage prostate cancer 60% Stage T4 20% Stage T3 20% Stage T2

7 History (Mid 20 th Century) Charles Brenton Huggins, M.D. Discovered hormonal therapy Survival improved by 5 10 years 1966 Nobel Prize in Medicine 1948 Autopsy Study for Prostate Cancer Second World War Advent of the modern resectoscope (TURP)

8 Transurethral Resection of the Prostate

9 Transurethral Resection of the Prostate

10 History (Mid 20 th Century) Routine Digital Rectal Examination Medical and Surgical Castration for T4 disease Incidental detection of Prostate Cancer TURP Has lead to a divergence between prostate cancer incidence and mortality Survival lead time bias Survival length time bias

11 Prostate Specific Antigen Serine Protease (Kallikrein 3) produced by normal and malignant prostate epithelial cells Found in 3 forms (bound to alpha 1 antichymotrypsin, bound to alpha 2 macroglobulin, free PSA) Liquefies seminal coagulum and cervical mucus Serologic assay developed 1979 (Wang) Used initially as a cancer marker to follow patients after radical prostatectomy (Stamey)

12 Prostate Specific Antigen Normal range ng/ml Lowered normal range to < 2.5 ng/ml for men with a positive family medical history of prostate cancer, men < 60 years of age, and African American men PSA rises < 0.5 ng/ml/yr (normal PSA velocity) Normal PSA density (PSA/Prostate Volume) is < 0.15 ng/ml/ml

13 Prostate Specific Antigen Measurement of Prostate Specific Antigen in Serum as a Screening Test for Prostate Cancer William J Catalona, M.D. et al. N Engl J Med 1991; 324: PSA % prostate cancer Biopsy performed only if an abnormal DRE or suspicious ultrasound PSA > % prostate cancer Abnormal DRE Control 24% prostate

14 Prostate Specific Antigen Sensitivity for prostate cancer (35 70%) Specificity for prostate cancer (60 90%) Biopsy sensitivity in screened men (60 80%) Elevated levels seen with Benign Prostatic Hyperplasia, Advanced Age, DRE, Urinary Tract infection, Prostatitis, GU instrumentation, Recent Sexual Activity

15 Number of New Prostate Cancer Cases and Deaths Per 100,000 Males (All Races), Age Adjusted Year New Cases Deaths Mortality Impact of PSA Screening on Prostate Cancer Specific

16 TRUS NBP

17 TRUS NBP

18 TRUS NBP

19 Prostate Cancer Grading

20 Prostate Cancer Clinical Staging T1a: Found incidentally on TURP, <5%, Normal DRE T1b: Found incidentally on TURP, >5%, Normal DRE T1c: Found on TRUS NBP for an elevated PSA, Normal DRE T2a: Palpable nodule on DRE, < ½ of one lobe T2b: Palpable nodule on DRE, > ½ of one lobe T2c: Palpable nodule bilaterally on DRE, both lobes T3a: Palpably outside the prostate but not seminal vesicles T3b: Palpably outside the prostate invading seminal vesicles T4: Locally invading the sphincter, rectum, bladder or pelvic wall

21 ACS Prostate Cancer Prognostic Groups Group 1 T1a c N0 M0 PSA < 10 Gleason <= 6 T2a N0 M0 PSA < 10 Gleason <= 6 Group 2a T1a c N0 M0 PSA < 20 Gleason 7 T1a c N0 M0 PSA >=10<20 Gleason <= 6 T1a c N0 M0 PSA >=10<20 Gleason <= 6 T2a N0 M0 PSA < 20 Gleason 7 T2b N0 M0 PSA < 20 Gleason <= 7 Group 2b T2c N0 M0 Any PSA Any Gleason T1 2 N0 M0 PSA > 20 Any Gleason T1 2 N0 M0 Any PSA Gleason >= 8 Group 3 T3 a b N0 M0 Any PSA Any Gleason Group 4 T4 N0 M0 Any PSA Any Gleason Any T N1 M0 Any PSA Any Gleason Any T Any N M1 Any PSA Any Gleason

22 National Comprehensive Cancer Network (NCCN) Prostate Cancer Risk Groups Low: PSA < 10 Gleason < 7 T1a c T2a Intermediate: PSA >= 10 < 20 Gleason 7 and/or T2b c High: PSA >=20 Gleason 8 10 T3

23 PSA Screening Trials European Randomized Study of Screening for Prostate Cancer (Europe) Prostate, Lung, Colon and Ovarian Cancer Screening trial (U.S.)

24 ERSPC: The European study Random assignment of men between 50 and 74 in 7 European countries Screened Group (83,000) received a PSA every 4 years Control Group (99,000) received standard of care (PSA not routinely utilized in Europe) Follow up 11 years

25 ERSPC Results Prostate cancer diagnosed in 9.6% of the screened group Prostate cancer diagnosed in 6.0% of the control group Screened group demonstrated a 29% prostate cancer specific mortality reduction compared to the control group Localized prostate cancer was more common in the screened group Goteborg Study (Sweden) demonstrated a 40% mortality reduction compared to control after 14 years

26 PLCO US Trial 76,693 men randomly assigned to either annual screening with PSA and DRE or usual care from Compliance rates for annual PSA and DRE were 85% and 86% respectively Usual care subjects included 52% receiving annual PSA and DRE with 92% receiving at least one PSA determination Follow up was 7 to 10 years Andriole GL, NEJM 2009; 360:

27 PLCO 2009 Results (7 Year Follow Up) Screened Group (38,243 subjects) Incidence of Prostate cancer: 116/10,000/Yr (2820 cases) Mortality of Prostate cancer: 2/10,000/Yr (50 deaths) Usual Care Control Group (38,350 subjects) Incidence of Prostate Cancer: 98/10,000/Yr (2322 cases) Mortality of Prostate Cancer: 1.7/10,000/Yr (44 deaths)

28 PCLO 2009 Conclusions Mortality rate was very low with no statistical difference between the study groups after 7 years of follow up Dr Andriole: Even if there was just a tiny mortality benefit [from prostate cancer screening], over diagnosis wouldn t be so bad if we didn t hurt people. But we do hurt people by finding a lot of trivial cancers that are most often over treated,

29 PLCO Criticism High rate of screening in the control group diluted results Follow up of 7 10 years not long enough to realize a mortality advantage from screening Using a PSA absolute value of 4.0 may lead to under diagnosis

30 United States Preventative Services Task Force Grade A (Recommended) There is high certainty that the net benefit is substantial. Should be covered by CMMS without a co pay Grade B (Recommended) There is high certainty that the net benefit is moderate or there is moderate certainty that the net benefit is moderate to substantial. Should be covered by CMMS with a co pay. Grade C (No Recommendation) Clinicians may provide the service to selected patients depending on individual circumstances. However, for most individuals without signs or symptoms there is likely to be only a small benefit. Not covered by CMMS. Grade D (Not recommended) The Task Force recommends against this service. There is moderate or high certainty that the service has no net benefit or that the harms outweigh the benefits.

31 United States Preventative Services Task Force Recommendations 2008: Against PSA screening for men >75 years October 2011: Draft recommendations against screening in all asymptomatic men May 2012: Final recommendations of Grade D for PSA screening in all men because the risks of screening outweigh the benefits Politically Motivated? Prostate cancer ~ $20 billion/yr

32 PSA Screening Dilemma 6% of men years of age have a PSA level greater than 4 or an abnormal DRE Would need to screen 250 men to find 15 men with an abnormal PSA or DRE for TRUS/NBP Would find 5 cases of prostate cancer in the 15 men undergoing a TRUS/NBP Would need to treat all 5 men to prevent one prostate cancer related death 3 men would survive regardless of treatment, 1 man would be saved and 1 would develop metastatic disease

33 American Urological Association Guidelines for Prostate Cancer Screening Recommends against PSA screening under 40 years of age Does not recommend routine PSA screening in men between 40 and 54 years of age with average risk (High risk: African Americans and those with a positive family history) For men between 55 and 69, the AUA recommends shared decision making between the patient and his physician regarding PSA screening Recommends a screening interval of 2 years as opposed to annual screening Recommends against PSA screening in men beyond 70 years or with a life expectancy less than years

34 The Holy Grail A test that is specific for prostate cancer One that differentiates between a potentially aggressive prostate cancer from an indolent malignancy Will detect such aggressive tumors at an early stage whereby treatment may reduce mortality

35 Oncology, Crawford et al, 2014 Other Biomarkers

36 Whom to Biopsy or Re Biopsy PSA Density > 0.15 ng/ml/ml PSA Velocity > 1.0 ng/ml/yr Free PSA Free / total PSA ratio years years > or =70 years < or = % 57.5% 64.5% % 33.9% 40.8% % 23.9% 29.7% > % 12.2% 15.8

37 Whom to Biopsy or Re biopsy Prostate Health Index (PHI) Formula combining total PSA, free PSA and [ 2] propsa For PSA > 2.0 <10 Probability for a positive biopsy: PHI % risk PHI % risk PHI % risk

38 Whom to Biopsy or Re biopsy 4K Score (4 prostate specific kallikreins) DRE yrs Total PSA, Free PSA, Intact PSA, beta Kallikrein 2 Algorithm: Patient age, History of previous biopsy and Helpful in predicting risk of aggressive prostate cancer Results on a scale from 0.0 (0% risk) 1.0 (100% risk) Results also correlate with the risk of metastases in 20

39 Whom to Biopsy or Re biopsy PCA3 Gene which expresses a non coding RNA only expressed in human prostate tissue and overexpressed with prostate cancer. Obtained from the first portion of a urine specimen after prostatic massage

40 Whom to Biopsy or Re biopsy PCA3 PCA3 Score Probability of prostate cancer on biopsy <5 14% % % % % >100 78%

41 Whom to Biopsy or Re biopsy SelectMDx MDxHealth Reverse transcriptase PCR performed on a urine specimen after prostate massage similar to PCA3 Measures mrna of DLX1 and HOXC6 over expressed in Gleason 7 for greater prostate cancer Algorithm also incorporates PSA, prostate volume, DRE, family history and patient age Reported as the percent risk for prostate cancer on biopsy and the percent risk for Gleason 7 or greater on bi

42 Whom to Biopsy or Re biopsy ConfirmMDx MDx Health Evaluates negative prostate biopsy tissue for DNA methylation of 3 prostate cancer genes: GSTP1, APC, RASSF1 Also incorporates patient age, PSA, DRE, histopathology of the previous biopsy (ie PIN, atypia) Results expressed as the risk of prostate cancer <= Gleason 6 and prostate cancer Gleason 7 or greater on repeat biopsy

43 Whom to Biopsy or Re biopsy ConfirmMDx

44 Whom to treat or not to treat OncotypeDX Genomic Prostate Score Predicts the likelihood of adverse pathology using 17 genomic pathways: AZGP1, FAM13C, KLK2, SRD5A2, FLNC, GSN, GSTM2, TPM2, BGN, COL1A1, SFRP4, TPX2, ARF1, ATP5E, CLTC, GPS1, PGK1 Assay is run on the malignant biopsy tissue Algorithm also incorporates patient age, race, PSA, clinical T Stage, biopsy Gleason Score and NCCN risk group

45 Whom to treat or not to treat OncotypeDx Genomic Health Designed for clinically low risk prostate cancer in patients who desire active surveillance. Results are reported as a GPS score (0 100) + NCCN risk Used to generate the percent likelihood of favorable pathology: low grade disease, organ confined disease

46 Whom to treat or not to treat Decipher GenomeDx Bioscience Based on the patient s tumor based genomic profile 1.4 million markers covering 46,000 coding genes Assay can be performed on either a biopsy or RP specimen Does not include clinical data to assess risk only genomics Predicts the probability of high grade disease (Gleason>7), 5 year risk for metastases, 10 year mortality risk Decipher score from Lower more favorable Genomic Resource Information Database (GRID) Large database of over 40,000 genomic profiles

47 Whom to treat or not to treat Prolaris Myriad Genetics Measures tumor cell growth characteristics for stratifying the risk of disease progression in prostate cancer patients. 46 gene expression signature includes cell cycle progression genes selected based upon correlation with prostate tumor cell proliferation: low gene expression associated with a low risk of disease progression high gene expression associated with disease progression. Also includes clinical data: Age, PSA, Gleason score, AUA risk, clinical T stage, number of positive cores, DRE Results reported as a Polaris risk score along with the 10 year mortality and metastatic disease risk

48 MRI TRUS Fusion Biopsy

49 MRI TRUS Fusion Biopsy

50 MRI TRUS Fusion Biopsy

51 MRI TRUS Fusion Biopsy Comparison of MR/ultrasound fusion guided biopsy with ultrasound guided biopsy for the diagnosis of prostate cancer JAMA Jan 27;313(4): Exact agreement between targeted and standard biopsy in 690 men (69%) undergoing biopsy Targeted biopsy diagnosed 30% more high risk cancers vs standard biopsy and 17% fewer low risk cancers Standard biopsy cores combined with the targeted approach diagnosed an additional 103 cases (22%) of prostate cancer

52 MRI TRUS Fusion Biopsy Negative prior biopsy with a continuing elevated or rising PSA Positive DRE with a negative TRUS biopsy Low grade / Low risk prostate cancer followed with active surveillance instead of repeated TRUS biopsy To diagnose a missed high grade cancer prior to planned active surveillance

53 Case One 47 year old Caucasian male who presents for urological evaluation after receiving a screening PSA of 2.6 detected during a life insurance physical examination. He is in otherwise good health with a negative FMH/O Prostate cancer. On DRE, his prostate is 25 gms, smooth without nodularity.

54 Case One A) Underwrite his insurance policy since his DRE is normal and he has no FMH/O CaP? B) Repeat the PSA after a 2 week course of antibiotics? C) Recommend a TRUS / NBP? D) Recommend a 4K Score, PCA3 or SelectMDX?

55 Case One After a 2 week course of Ciprofloxin 500 mg po bid and abstention from sexual activity for 72 hours his repeat PSA remains stable at 2.6 ng/ml

56 Case One A) Underwrite his policy? B) Recommend a TRUS/NBP because of his age? C) Recommend repeating a PSA in 6 months? D) Recommend a 4KScore, PCA3 or Select MDx test?

57 Case One His life insurance company insisted that a TRUS/NBP be performed to rule out prostate cancer. The biopsy revealed one of twelve cores positive for Gleason 2+3 in less that 5% of the core without perineural invasion. His metastatic evaluation which included a bone scan and Abd/Pevic CT with contrast were both negative.

58 Case One A) Underwrite his policy? B) Recommend curative treatment with either a radical prostatectomy or XRT? C) Recommend a Oncotype Dx or Prolaris test on the specimen? D) Place the patient on active surveillance and repeat a TRUS / NBP in one year?

59 Case One The patient under went a nerve sparing radical retropubic prostatectomy with complete preservation of sexual function and urinary control. The pathology report showed a single focus of Gleason 3+3 at the right base with negative margins, no perineural invasion, negative seminal vesical and lymph node involvement. His first PSA 3 months post op was <0.05 ng/ml and has remained undetectable for 20 years.

60 Case Two 72 year old Caucasian male who was found to have a prostate nodule on DRE. His physician immediately drew a PSA which returned elevated at 7.3 ng/ml. His last PSA was 2.4 ng/ml in 2012 but was advised against further annual PSA screening because of the new USPTF guidelines. He is good health with mild HTN and served two combat tours in Vietnam having been exposed to Agent Orange with both tours. He was also treated for 2 STDs while in the service.

61 Case Two A) Reassure the patient that a mildly elevated PSA may be normal for a male over the age of 70? B) Repeat a PSA along with a free PSA after a course of antibiotics and prior to a DRE? C) Recommend a 4KScore, PCA3 or Select MDX Test? D) Recommend a TRUS/NBP?

62 Case Two Repeat total and free PSA after a 2 week course of ciprofloxin was 5.7 ng/ml and 15% respectively. His DRE demonstrated a firm nodule at the left base. Prostate ultrasonography showed a volume of 55 ml with diffuse calcifications consistent with chronic prostatitis.

63 Case Two A) Reassure the patient since his PSA fell on antibiotics and repeat a PSA in 6 months? B) Recommend a 4KScore, Select MDx or PCA3 test? C) Recommend a TRUS / NBP because of the persistently elevated PSA, the borderline free PSA, the prostate nodule, and his prior exposure to Agent Orange?

64 Case Two The patient underwent a TRUS / NBP which revealed Gleason 3+4 and 4+3 adenocarcinoma in all 12 cores with diffuse perineural invasion. His metastatic workup which included a bone scan and Abd/Pelvic CT were both negative.

65 Case Two A) Recommend a radical retropubic prostatectomy (may need adjuvant XRT) B) Recommend XRT +/ Hormonal therapy for 3 years C) Recommend a Oncotype DX test? D) Recommend Active surveillance?

66 Case Two The patient was started hormonal therapy (Lupron + Casodex) and is scheduled to begin IMRT radiation therapy (40 treatments) in 3 weeks. He will be maintained on hormonal therapy for 3 years.

67 Case Three 52 year old African American male with a strong family medical history of prostate cancer (father, brother, paternal uncle) but in excellent health seeking a whole life insurance policy. He underwent a screening PSA which was 1.2 ng/ml and had a normal DRE.

68 Case Three A) Underwrite his policy? B) Insist on a TRUS/NBP C) Recommend following the patient with annual PSA screening reserving a biopsy if > 2.5 ng/ml? D) Order a Select MDx, PCA3 or 4Kscore?

69 Case Three PSA year ng/ml normal DRE PSA year ng/ml normal DRE PSA year ng/ml normal DRE Prostate volume 14 ml PSA density: 0.17 Normal echo structure on TRUS

70 Case Three A) Underwrite his policy? B) Recommend a TRUS / NBP because of the strong family history and the borderline PSA density? C) Recommend a 4Kscore, Select MDx or PCA3 test?

71 Case Three The patient underwent a TRUS / NBP which was benign. A) Underwrite his policy? B) Recommend a Confirmed MDx test on the specimen? C) Continue to follow with annual PSA screening?

72 Case Three The patient s biopsy specimen was submitted for Confirmed MDx: Left Mid core: + GSTP1 Methylation + APC Methylation + RASSF1 Methylation 10.2% Probability of prostate cancer on a repeat biopsy

73 Case Three Repeat biopsy performed 6 months later showed one core with atypia at the left mid region. Pre biopsy PSA 2.8 ng/ml A) Underwrite his policy? B) Recommend a MRI TRUS fusion biopsy? C) Continue to follow the patient?

74 Case Three Four months later, the patient underwent a T3 MRI TRUS fusion biopsy. There was a focus seen at the left anterior region. He underwent multiple biopsies of this region along with the standard template and all specimens were negative. He stated in the recovery room, I won t need a life insurance policy if I ever go through that again.

75 Case Four 56 year old African American male with mild hypertension and hyperlipidemia both controlled with medication who presents with a PSA of 6.2 ng/ml and moderate LUTS from BPH. DRE revealed a moderately enlarged benign feeling prostate. He was initially treated with tamsulosin and a 2 week course of ciprofloxin. His repeat PSA then dropped to 5.7 ng/ml and a prostate ultrasound revealed a 43 ml gland with diffuse calcifications consistent with chronic prostatitis. His LUTS had improved.

76 Case Four A) Recommend a TRUS / NBP? B) Follow the patient with a repeat PSA in 6 months? C) Recommend a Select MDx Test? D) Recommend a TURP for his LUTS?

77 Case Four His prostate biopsy demonstrated benign tissue with chronic inflammation. Prostate volume was measured at 62 ml with central calcifications but which a normal echotexture. A repeat PSA 6 months later has risen to 7.9 ng/ml with a free PSA of 11 %

78 Case Four A) Recommend a repeat TRUS /NBP? B) Repeat the PSA after a 2 week course of antibiotics? C) Continue to follow with a repeat PSA in 6 months? D) Recommend a SelectMDx, PCA3 or a 4KScore?

79 Case Four He had elected to follow his PSA which was now elevated at 10.8 ng/ml A Confirmed MDx test on the previous biopsy cores was performed which demonstated no DNA methylation

80 Case Four He again was followed for 6 months and now his PSA had risen to 17.9 ng/ml. Additionally, his LUTS had worsened and dutasteride was added to his regimen of tamsulosin resulting in slight improvement of his symptoms. A repeat PSA 3 months later was now 18.2 ng/ml.

81 Case Four A) Recommend an MRI TRUS fusion biopsy? B) Recommend a TURP to obtain tissue and to relieve his LUTS? C) Recommend a Select MDx, PCA3 or 4KScore test? D) Continue to follow the patient?

82 Case Four A repeat prostate biopsy was performed and was again negative but with one core demonstrating atypia and 2 cores with high grade PIN. His LUTS continued to worsen eventually progressing to frank urinary retention requiring foley catheter insertion

83 Case Four A) Recommend a minimally invasive office based treatment for BPH such a TUMT, TUNA, Rezume, UroLift? B) Recommend a minimally invasive TUR such a laser TURP, HoLap, Plasma button photovaporization? C) Recommend a standard TURP?

84 Case Four The patient underwent a standard TURP which revealed 26 chips out of 337 positive for Gleason 3+4 adenocarcinoma. The months later he underwent a radical prostatectomy to remove the remaining prostate which showed that the tumor was confined to the anterior region of the prostate and would not have been diagnosed on subsequent peripheral zone biopsies. The patient s PSA remains undetectable after 3 years and voids well off medication.

85 Case Five 73 year old Caucasian male referred for the evaluation of a mildly elevated PSA of 4.6 ng/ml. He was also experiencing moderate LUTS with intermittent gross hematuria. DRE revealed a rock hard fixed prostate worrisome for malignancy. He was scheduled for a CT Urogram and cystoscopy to evaluate his hematuria along with a TRUS / NBP.

86 Case Five His CT Urogram was unremarkable aside from adenopathy noted along the left pelvic lymph nodes. Cystoscopy revealed friable inflammation within the prostate urethra and bladder neck. Urine cytologies were atypical. A TRUS/NBP was performed which reveal a mixed hypoechoic prostate with indistinct borders. Pathology retuned positive for Gleason 4+3 adenocarcinoma in all 12 cores. His bone scan was negative for metastases. Prostatic acid phosphatase was within normal limits

87 Case Five A) Recommend a radical retropubic prostatectomy with extensive bilateral pelvic and external iliac lymphadenectomy followed by adjuvant radiation therapy? B) Recommend combined hormonal therapy with external beam radiation therapy including the pelvic adenopathy? C) Recommend Hormonal therapy only because of obvious nodal disease?

88 Case Five The patient is started on Leuprolide + Bicalutamide and his PSA drops to an undetectable range of <0.1 ng/ml. However over the subsequent few weeks, the patient continued to progress with weight loss and anorexia. He was hospitalized with ARF, bilateral hydronephrosis, worsening lower extremity edema and was found to have diffuse pulmonary metastases. Interestingly, his bone scan remained negative.

89 Case Five He progressed to urinary retention requiring that a channel TURP be performed since he did not tolerate a foley catheter. The pathology again demonstrated Gleason 4+3 adenocarcinoma identical to the TRUS / NBP. Immunohistochemical stains were requested because of the atypical manner in which the patient has progressed

90 Case Five Immunohistochemical Analysis: PSA, PSAP Negative CK7, CK28 Strongly positive P63, GATA3 Positive TTF, PAX8, CDX2, P504 Negative Finding consistent with a primary urothelial malignancy not prostate adenocarcinoma