prostate cancer update 2016 - acofp · prostate cancer update 2016 ronnie b. martin, do, facofp...
TRANSCRIPT
·:{iC0Fp'16ACOFP 53rd Annual Convention & Scientific Seminars
Prostate Cancer Update 2016
Ronnie Martin, DO, FACOFP dist.
ACOFP FULL DISCLOSURE FOR CME ACTIVITIES
Please check where applicable and sign below. Provide additional pages as necessary.
Name of CME Activity: ACOFP 53rd Annual Convention and Scientific Seminars
Dates and Location of CME Activity: April 6-9, 2016, The San Juan Puerto Rico Convention CenterYour presentation: Friday, Apri 2016 7:00am-8:00am; Men's Health: Prostate
DISCLOSURE OF FINANCIAL RELATIONSHIPS WITHIN 12 MONTHS OF DATE OF THIS FORM
\/ A. Neither I nor any member of my immediate family has a financial relationship or interest with any proprietary entity producing
--J:-- health care goods or services. 8. I have, or an immediate family member has, a financial relationship or interest with a proprietary entity producing health care
goods or services. Please check the relationship(s) that applies. Research Grants Stock/Bond Holdings (excluding mutual funds)Speakers' Bureaus•OwnershipConsultant for Fee
EmploymentPartnershipOthers, please list:
Please indicate the name(s) of the organization(s) with which you have a financial relationship or interest, and the specific clinical area(s)that correspond to the relationship(s). If more than four relationships, please list on separate piece of paper:
Organization With Which Relationship Exists Clinical Area Involved
1. 1.
2. 2.
3. 3.
4. 4.
*If you checked "Speakers' Bureaus� in item 8, please continue:Did you participate in company-provided speaker training related to your proposed Topic?Did you travel to participate in this training?Did the company provide you with slides of the presentation in which you were trained as a speaker?Did the company pay the travel/lodging/other expenses?Did you receive an honorarium or consulting fee for participating in this training?Have you received any other type of compensation from the company? Please specify:When serving as faculty for ACOFP, will you use slides provided by a proprietary entity for your presentationand/or lecture handout materials?Will your Topic1 involve information or data obtained from commercial speaker training?
Yes:Yes:
Yes:Yes:
Yes:Yes:
Yes:Yes:
DISCLOSURE OF UNLABELED/INVESTIGATIONAL USES OF PRODUCTS __){_A. The content of my material(s)/presentation(s) in this CME activity will not include discussion of unapproved or
investigational uses of products or devices.
No:No:No:No:No:No:
No:No:
___ B. The content of my material(s)lpresentation in this CME activity will include discussion of unapproved or investigationaluses of products or devices as indicated below:
I have read the ACOFP policy on full disclosure. If I have indicated a financial relationship or interest, I understand that thisinformation will be reviewed to determine whether a conflict of interest may exist, and I may be asked to provide additionalinformation. I understand t failure or refusal to disclose, false disclosure, or inability to resolve conflicts will require the ACOFP to identify acement.
Signature:
Ronnie Martin, DO, FACOFP, dist.
Please email this form to [email protected] as soon as possible Deadline: Friday, January 15. 2016
3/17/2016
1
Prostate Cancer Update 2016
Ronnie B. Martin, DO, FACOFPDean Liberty University College of
Osteopathic Medicine
Prostate cancer
33% of the none cutaneous malignancy’s in men inUSA.
2nd most common cause of cancer deaths in men.
In 2015 expected >220,000 newly diagnosed cases inthe U.S.
27,500 will die of P-Ca 2015, less than 2005 in spite ofincreased diagnosis of disease.
Prostate cancer
Ethnic and genealogical propendency:– African Americans having highest incidence in world (224 cases
per 100,000 vs. White Americans at 150/100,00, Japanese at 8.5/100,000 and Chinese at 1.1.
– Genetic link with familial pattern demonstrated
– Environmental link less clearly established
3/17/2016
2
Prostate cancer diagnosis peaked in1993 at > 350,000 with advent of PSAtesting.
Lifetime odds of developing P-Ca is 1:8to 1:14.
Mortality from prostate cancer declined2.6% each year 1990 to 1998 but hasplateaued since then.
Prostate cancer
Identified risk factors include:
– Advancing Age
While q.s. 20% Men < 40 demonstratehistological evidence of CA, clinical disease rare
20-30% of men > 50 have histologicalevidence of disease
> 50% of men > than 80 years of age havehistological disease
Prostate cancer
Identified risk factors include:– Family History
Men with first degree relatives with P-CA have2 to 3 fold increase risk, men with two or morefirst degree relatives have 5 fold increased risk.
Familial prostate cancer estimated 5 to 10% oftotal cases and q.s. 50% of cases in men lessthan 55 years old.
– Genetic Factors Androgen receptor gene CAG sequence repeats
(AA have fewer repeats)
3/17/2016
3
General Information
Rarely found in men younger than 40
Vasectomy - recent studies have not foundincreased risk
No correlation with BPH
Prostate cancer
Identified risk factors include:
– Diet
Red meat, animal fat and higher total fat, andhigh calcium intake all increase risk.
Lycopene, selenium, fatty fish, Vitamin E, soyand Vit. D may help decrease risk
– Hormone Levels
Androgen level elevation, especially freetestosterone, increases risk
Screening for Prostate Cancer
Goal is to detect organ confined prostatecancer (potentially curable stage).
Digital Rectal Examination is foundationof diagnosis but inadequate alone:– Interpretation variable among physicians
– majority of cancers not palatable beforemetastatic.
3/17/2016
4
Screening for Prostate Cancer
Prostate Specific Antigen:– Produced by both normal and malignant prostate
epithelial cells (rate of release into serum in P-CAis 30x higher)
– Also produced by seminal vesicles, breasts,adrenals, parotid, etc.
– Elevated by inflammation, infection, ejaculation,instrumentation, trauma, and increased glandmass such as found with BPH BPH is most common cause of elevated serum PSA.
PSA
Normal range 0 - 4 ng/ml ( Complexed measurement) “gray zone” 4 - 10 ng/ml
– Chances of finding CA in this “gray zone” ranges from 25 to30%
– Recommended that you perform free PSA when levels in gray zone if no other findings.
Predictable CA (> 60%) when PSA > 10 ng/ml Can obtain these levels from BPH, prostatitis, orchitis, etc.
Can make more specific with calculations such as:Free PSA
– PSA velocity– PSA density
Screening for Prostate Cancer
Screening for prostate cancer combinesuse of PSA and DRE– Today, more cancers detected are organ
confided with use of combined diagnosistechniques and more screening.
– PSA will detect CA an average of 5.5 yearsbefore clinical detection alone.
3/17/2016
5
Screening for Prostate Cancer
American Urological Society recommends shareddecision between Doctor and patient about annualDRE and PSA for men older than 55 who otherwisehave a life expectancy of >10 years.– Epidemiological studies do not support implementation of
routine PSA screening of low risk asymptomatic men under40-54.
– Screening is not indicated for men >69 or those with less than 10 year life expectancy, recognizing that some men >70 with projected life expectancy > 10 years may benefit.
If PSA is < 2.5 then screening if elected should bedone no more often then every two years.
Screening for Prostate Cancer
High Risk Patients: especially African American Malesand those with family history, screening may begin asearly as age 40 or < 54 years of age– Annual screening being challenged, some recent mega-
analysis show that screening at 40 and if normal again at 45and then only every 2 years produce less morbidity and similar mortality outcomes.
Problems with PSA and DRE Combined Screenings
Lack of specificity between 4 and 10 leads to mixresults:– Unnecessary treatment for insignificant cancers with
increased morbidity and cost.– Most levels in this range are BPH on biopsy
morbidity and cost of biopsies is significant.
PSA > 10 generally CA but also most often organconfined cancer.
10-15% of P-CA will have PSA level of < 4 and willnot be palpated by DRE.– These malignancy’s tend to higher grade as well.
3/17/2016
6
Compensations for PSA
Age specific PSA:
– Especially important in younger men wherethreshold of 2.6 ng/ml has been advocated formen < 50.
– Less sensitivity in older men if raise level and maymiss non organ confined disease if > 4 ng/ml.
Race Specific PSA:
– AA males have base line levels higher than whitemales.
Compensations for PSA
PSA Velocity:– Measure rate of increase in PSA.– Doubling time is correlated with mortality and morbidity as
well as response to therapy. Especially useful in younger men with normal or “grey
area” PSA readings. PSA increase of > 2.0 ng/ml in year prior to surgery was
significantly associated with lymph node metastases and high grade disease and higher mortality, reoccurrence.
PSA doubling time found to be independent predictor oftime to development of metastatic disease. < 3 month doubling time was significantly associated with death from prostrate cancer ( 20x the risk of other patients).
Compensations for PSA
PSA Density:– Higher PSA/volume of gland with CA is supposed to reflect
more accurately elevations. Problem is measurement of gland volume via TRUS and few
studies have documented value.
Free PSA:– Percentage of PSA not bound to serum proteins.– Normally 30-40% of total.– Men with P-CA have less free PSA and higher levels of
complexed PSA. – The lower the % of free PSA, the more likely malignancy.– With threshold of 20-25% of Complexed PSA, accurate 90%
of time in predicting cancer.
3/17/2016
7
Partin Tables, Kattan Nomogram, D’Amico’s Model
Prognostic models that combine 3 or moreindependent variables, useful in predicting outcomesand may direct management.– Partin utilizes PSA, clinical stage and Gleason score to
predict organ confined disease vs. cancer spread to seminal vesicles or lymph nodes.
Accurate in independent studies to stage tumor 70-80% of the time.
– D”Amico uses preoperative PSA, Gleason, AJCC tumor stage to predict 10 year PSA failure free survival post radical prostatectomy.
10 year PSA free rate in those classified as low risk was 83%, 46% in those in intermediate risk and 29% in those in high risk categories.
Patients may live years after reappearance of PSA.
Disease Markers Under Investigation:
IGF-1--Insulin like growth factor,increase associated with P-CA
Prostate specific membrane antigen –PSMA—Detected with ProstaScint, maydiscriminate BPH, CA and no disease.
Telomerase activity—present in majorityof CA patient but not in benign prostatetissues.
Prevention of Prostate CA
Study using finasteride, a 5-alphareductase inhibitor that lowertestosterone conversion to DHEAdemonstrate ~25% reduction inprostate CA after 7 year follow up.– Those cancers that did develop were much
higher grade and aggressive
– Side effects were significant and oftenprecluded completion of study.
3/17/2016
8
Diagnosis of Prostate Cancer
Prostate Biopsy is cornerstone:
– Generally do a min. of 6 biopsies to cover all areasof gland
– Indicated with elevated PSA, abnormal DRE orboth.
Biopsies are guided by Trans-Rectal U.S.
– TRUS by itself is not reliable screen or diagnostic ofP-CA.
– TRUS helpful in determining volume of gland andcalculating volume adjusted PSA.
Pathology
Overwhelming adenocarcinoma,occasional small cell or sarcoma
70% of prostate cancers arise in theperipheral zone
15 - 20% arise in the central zone
10 - 15% arise in the transition zone
Pathology - Gleason Grading System
Based on glandular disorganization in architecture on examination of biopsy.
Tumors are graded 1 to 5 and total of the two most common added together to get Gleason Score.
2 - 4 well-differentiated 5 - 7 moderately differentiated 8 - 10 poorly differentiated Utilization limited by rarity to get score of less than 6. Clinically differentiation is:
– Low grade< 6.– Intermediate grades 6 to 8 – High grade > 8
For staging and prognosis charts.
3/17/2016
9
Staging of Prostate Cancer
Purpose is to determined if organ confined(thus potentially curable) or not organconfined.– Local spread to capsule, seminal vesicles and local
lymph nodes
– Disease’s tendency is to metastasis to bone, lymphnodes Rare today to make diagnosis through evidence of boney
mets.
– Rarer to have metastasis to visceral organs suchas lung or liver
Staging of Prostate Cancer
Clinical Staging:
Localized tumors are T1 and T2.– Potentially curable with surgery or radiation.
Local advanced tumors are T3 and T4.– Rarely curable by surgery or radiation alone
Today, with aggressive utilization of PSA,most commonly cancers detected are nonpalatable T1c cancers.
Multifactorial Staging of Prostate Cancer
Combines use of clinical staging,Gleason score and serum PSA level.– Useful to determine if low, moderate or
high risk of relapse after therapy.
Prognosis worse if PSA increased bymore than 2 ng/ml in year precedingdiagnosis of P-CA
3/17/2016
10
Multifactorial Staging of Prostate Cancer
Bone Scan, and MRI or CT useful inpatients with prostate CA and serumPSA level > 10 ng/ml, Gleason score 7to 10 or who have T3 or T4 tumors tofind regional lymph node and boneyspread.
Symptoms of Prostate CA
P-CA rarely causes local symptoms untilvery large or advanced.
– S/S are more common with BPH.
urinary hesitancy
post void dribbling
urinary retention
hematuria
incontinence
Metastatic Prostate CA Symptoms
Bone pain
Neurological symptoms secondary tocord compression
Pathologic fractures
3/17/2016
11
Treatment for Prostate CA: Observation Indications & Natural
Progression
In cases with high grade tumors (Gleasonscore >/= 7) and patient < 74, the patientshould be treated.
All tumors with Gleason score of >/= 7should be considered high grade tumors andshould be treated.
Patient’s age at diagnosis appears to havelittle impact on 15 year mortality regardlessof low grade or high grade tumor.
Treatment for Prostate CA: Natural Progression and Observation
Age at diagnosis can lead to determination oftreatment if locally confined.
10 year prognosis same with treatment orwithout treatment is essentially the same inthe Connecticut Tumor Registry Study and theSEER date bases (Surveillance, Epidemiology,and End Results database):– 70 year old man has 13.6 years of life expectancy.
– 75 year old man has 10.8 years of life remaining
– 80 year old man has 8.1 years of life remaining
Treatment for Localized Prostate Cancer (T1 &T2)
Treatment decisions generally made bypatient based on physicians bias sincethere is an absence of randomizedstudies showing a therapeuticsuperiority for surgery or radiationtherapy present in compatiblepopulations.
3/17/2016
12
Treatment for Localized Prostate Cancer (T1 &T2)
Radical Prostatectomy– Most common treatment in US for localized disease
– Retropubic approach most common since allows possibility of lymph node dissection [extended pelvic lymphadenectomy], preservation of nerves and wide resection margins.
– Side effects and complications of urinary incontinence ( 5-35% of patients), sexual dysfunction (50-75% of men) largely based on skill of surgeon
– Use of nerve sparing techniques, robotics et al have improved co-morbidities, blood loss, side effect static's but
only a little.
Treatment for Localized Prostate Cancer (T1 &T2) Radiation Therapy
– Computer aided 3-D conformal treatment availabletoday allows higher doses than traditional 7000rads, fewer side effects and better chance of curetoday.
– Side effects and efficiency both considerations– Rectal injury’s seen more commonly than with
surgery with tenesmus, proctitis, colitis, bleedinget al.
– Urinary incontinence (including urgency,frequency, hematuria) and erectile dysfunctionless common than produced by surgery but stillpresent in majority of patients.
Treatment for Localized Prostate Cancer (T1 &T2) Observation:
Low risk patients, localized tumor, lowcombined Gleason and PSA scores.
– Outcome at 10 years same with NOtreatment as with radiation or surgery inmeta analysis of studies.
3/17/2016
13
Treatment for Localized Prostate Cancer (T1 &T2)
Brachytherapy:– Implantation of I-125 (slower growing) or
Palladium 103 (higher grade tumors) seeds intotumor.
– Advantage: Ease of treatment (one step),favorable toxicity profile
– Concerns: May leave “cold spots” that allowcancer persist or grow.
– Better static's in intermediate and high riskpatients if combined with external radiation andhormone manipulation.
Treatment for Localized Prostate Cancer (T1 &T2)
Cryotherapy– Becoming utilized again with better probes and
less localized damage due to technique. Works bylocal destruction and possibly activation ofimmunological system
Hormonal therapy– More commonly adjunctive therapy in early stages
because of anticipated loss of response andchance of cure with other therapy.
– More common as palliative therapy in advancedcases in USA.
Management of Intermediate Risk Patients
Higher cancer volume, occult metastatic risk higheror spread already apparent.
Surgery is still curative in locally spread cases about50% of the time.– Little benefit demonstrated by using androgen ablation
before surgery to reduce tumor size.
Combined external beam radiation and brachytherapyused in some cases with mixed results.
Combined external bean radiation and androgenablation has been shown to provide survival benefitin intermittent risk patients.
3/17/2016
14
Adjunctive Therapy and Relapse Therapy:
Radiation after surgery is beneficial for:– Adverse pathological finding such as not clean margins,
capsular penetration, seminal vesicle involvement.
Rising PSA post operatively is indication for radiationadjunctive therapy &/or hormonal manipulation:– Prognosis is predicted by several factors:
time to rise in PSA (> 2 years better)
Serum PSA < 1 ng/ml at time of salvage radiation therapy
Adjunctive Therapy and Relapse Therapy:
Androgen ablation has been useful aftersurgery or radiation.
– Three years of androgen deprivationtherapy demonstrated statically significant
improvement in outcome in men treatedwith radiation in recent European study.
Management of Patients with Advanced or Metastatic Cancer (T3
or T4)
Local therapy alone rarely curative, therefore the morbidity of surgery rarely justified.
Most treated with combined androgen ablation followed by external beam radiation therapy.
3/17/2016
15
ANDROGEN ABLATION THERAPY
Prostate cells require androgen forgrowth and survival
Two mechanism of therapy:
– Lower the production of testosterone
– Blockage of the binding to androgen
receptor
ANDROGEN ABLATION THERAPY
PSA drops rapidly
Symptoms from metastases lessen or disappearrapidly
Androgen ablation is palliative rather than curative.– Duration of response, dependent on androgen sensitivity of
the tumor, before first rise in PSA being noted is generally 12to 18 months if patients had metastasis at initiation of treatment, much longer if no metastasis present.
ANDROGEN ABLATION THERAPY
Castration: Surgical or chemical.
Orchiectomy– Often not well received by many patients due to
emotional trauma, side effects, sexual deficits, hotflashes, loss of muscle tone, weight gain etc.
LH-RH Agonists – block production at pituitaryof releasing hormones and thus decreaseproduction of testosterone at end organ.
– Leuprolide (Lupron) , Goserelin (Zoladex)
– Administered every 1 to 4 months
3/17/2016
16
Side Effects of LH - RH Agents
Hot flashes
Night Sweats
Testicular atrophy
Sexual dysfunction; decreased libido and impotency
Nausea
Gynecomastia
Weight Gain (adipose fat leads to risk of diabetes)
Loss of bone and muscle mass with resultantosteoporosis, fractures, etc.
ANDROGEN ABLATION THERAPY
Antiandrogens – Flutamide (Eulexin),Bicalutamide (Casodex) and Nilutamide(Nilandron)
Inhibits androgen uptake and binding toandrogen receptors.
Timing of Ablation Therapy
Early androgen suppression has beenshown to reduce disease progressionand related complications and slightlyimprove 10 year survival rate in patientwho had either surgery or radiation forlocally advanced or metastatic prostatecancer.
3/17/2016
17
Optimal Androgen Deprivation Therapy
Antiandrogen monotherapy appears to beinferior to LHRH agonist, orchiectomy orestrogens alone in patients with knowadvanced disease.
Recent study analysis have concluded that ifcombined androgen blockade [use ofleuprolide plus flutamide] (CAB) does benefitpatients with established mets, the benefit is
“extremely modest”.
Adjunctive Prostate CA Therapy
Estrogen: Diethylstilbestrol lowers LH levels and mayhave direct effect on cancer cells.– Increased thromboembolic risk and cardiovascular effects
have caused loss of use in US.
Gn-RH – antagonist – Abarelix (Plenaxis) limitedavailability in US
Zoledronic Acid (Zomeda) interferes with Cametabolism and interferes with boney reabsorptiondue to orthoclastic activity.
Chemotherapy
Established role in hormone refractory prostatecancer.
Mitoxantrone (Novantrone) approved by FDA fortreatment of hormone refractory prostate cancer.[Use in conjunction with corticosteroids]
Taxanes: Docetaxel (Taxotene) and Paclitaxel (Taxol)– Inhibit mitosis in prostate epithelial cells.
– Docetaxel plus prednisone in accepted as standard chemotherapy for men with metastatic prostate cancer.
3/17/2016
18
Chemotherapy
Cyclophosphamide
methrotrexate
5 - fluorouricil
Newer Therapies for Prostate Cancer
Tyrosine kinase inhibitors andproteasome inhibitors used incombination with chemotherapy.
Endothelin-1 inhibitor (Atrasentan)
Angiogenesis inhibitors.
Therapeutic vaccines and monoclonalantibodies.
Palliative Therapy
Localized radiation for bone pain atspecific sites of mets.
Radiopharmaceuticals such asStrontium 89 or Samatium-153concentrate in osseous tissue and areused to treat multiple sites of pain.
Analgesics-NSAID or Opioids
TURP-for obstruction problems