Prostate Cancer Update 2016 - ACOFP · Prostate Cancer Update 2016 Ronnie B. Martin, DO, FACOFP Dean Liberty University College of Osteopathic Medicine Prostate cancer 33% of the

·:{iC0Fp'16ACOFP 53rd Annual Convention & Scientific Seminars

Prostate Cancer Update 2016

Ronnie Martin, DO, FACOFP dist.

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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

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Ronnie Martin, DO, FACOFP, dist.

Please email this form to [email protected] as soon as possible Deadline: Friday, January 15. 2016

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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

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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)

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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.

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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 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.

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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.


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.

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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.


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).


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.

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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.

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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.

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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

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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

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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.

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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.

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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.


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.

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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.

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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


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.


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

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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.


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.

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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.

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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

Documents

Prostate Cancer Update 2016 - ACOFP · Prostate Cancer Update 2016 Ronnie B. Martin, DO, FACOFP Dean Liberty University College of Osteopathic Medicine Prostate cancer 33% of the