Prostate cancer

Estimated 31,000 deaths in 2019 from prostate cancer, and 174,650 new cases.

The median age at which men die from prostate cancer in the United States is 80.

The most common noncutaneous malignancy in men.

In 2018 an estimated 1.28 million new cases were diagnosed with approximately 359,000 deaths, worldwide.

Second most commonly diagnosed malignancy after skin cancer.

Second most common cause of cancer death in men.

Becomes lethal when the disease becomes castration resistant and widely metastatic.

70% of patience with a  new diagnosis have localized disease.

Following prostatectomy or radiation, 20-40% and 30-50% of patients develop recurrence, respectively.

Up to 30% of patients initially diagnosed with and treated for localized prostate cancer develop metastases.

Nearly 6% of men have distant metastases a diagnosis with a five-year survival of 30%.

10-20% of patients with advanced prostate cancer progress to castration-resistant disease in 5 years after an initial response to hormonal treatment, and these patients have a much poorer prognosis than those with hormonal dependent prostate cancer.

Radical prostatectomy or radiation therapy with or without androgen deprivation therapy are often curative treatments for localized disease, however approximately 1/4 of patient will experience recurrence within 10 years after curative intent therapy.

Randomized trials comparing radical prostatectomy with external beam radiotherapy for the treatment of men with favorable prostate cancer has shown equivalent results.

In a randomized study of radical prostatectomy versus a combination of external beam radiotherapy, btachytherapy and androgen deprivation therapy in patients with high risk of prostate cancer with Gleason score 9-10 Prostate cancer showed equivalent prostate cancer specific mortality risk and all cause mortality risk (Tolkien D).

Prostate cancer cells must regulate and degrade the androgen receptor if they are to proliferate.

In a low testosterone environment of androgen deprivation therapy, prostate cancer cells adapt to produce far more androgen receptor, allowing them to capture every possible molecule of testosterone.

Androgen receptors mutate so they function even in the absence of testosterone.

Behavior ranges from indolent to aggressive.

Aggressive prostate cancer criteria include:histological small cell prostate cancer, visceral only metastases, osteolytic bone metastases, greater than 5 cm bulky lymphadenopathy or primary tumor, low PSA antigen plus high-volume bone metastases, elevated LDH or CEA, or short response to primary androgen deprivation therapy.

High-volume prostate cancer is defined as that in which patients have either visceral metastasis or four or more bone metastasis, at least one of which is outside vertebral column or pelvis.

It is estimated that bone metastases developed in 1/3 of patients with non-metastatic, castration resistant prostate cancer within two years after diagnosis.

In 2014 accounted for 27% of non-skin cancers in men in the US.

Lifetime risk of PC 17% and 3% lifetime risk of PC death.

Almost 3,000,000 survivors with prostate cancer in the US, making up 45% total male cancer survivor population.

Small amounts of low-grade prostate cancer can be found in 30% of men over the age of 50.

Arises from genetically altered prostate epithelium and slowly progresses over several decades.

Its multifocality and heterogeneity makes its course difficult to predict.

Male infertility associated with a higher risk.

Most cases are localized cancers, which are stratified into low, intermediate, and high risk disease based on their prostate cancer specific mortality.

The NCCN risk classification: divides risk into very-low, low, intermediate, igh and very-high risk groups.

NCCN system defines intermediate risk prostate ca as having at least one of the following:

clinical tumor stage T2b or T2c, Gleason score 7, PSA 10-20 ng/mL.

6% present with metastatic disease.

Up to 2015, the five-year survival rate was approximately 31% of patients with metastatic disease.

In the prePSA era regional or metastatic disease was seen in 25% of men with prostate cancer.

Clinical prognosis groups are based on pretreatment PSA, biopsy based Gleason score,and TNM staging.

Rapid PSA doubling time (? 10 months) is predictive of the development of metastatic disease in patients with nonmetastatic castrate resistant PC.

Intermediate-risk PC is the largest risk group with marked heterogeneity in prognoses, and wide range of cancer specific mortality and clinical recurrence rate after treatment.

The strongest evidence of reduction in mortality PC is for intermediate to high risk disease with Gleason scores 7 to 10 in which randomized clinical trials shows benefits of therapy with radiotherapy or surgery.

Comparing modern radiotherapy to radical prostatectomy the former is better in terms of urinary and sexual function.

Bowel toxicity has been mitigated largely by using modern radiotherapy techniques.

Quality of life following radiotherapy has improved with modern radiotherapeutic techniques, whereas prostate surgery complications remain largely unchanged in regard to long-term impact.

Patients who undergo radical prostatectomy are typically younger and have fewer comorbidities, and have better baseline sexual function and physical function overall in patients who undergo radiation.

Between 30-40% of prostate glands in men over the age of 50 harbor microscopic foci of Gleason’s 6 at autopsy indicates that they appeared to be of no clinical significance.

It is likely that a substantial portion of patients with prostate cancer the process will never become clinically significant.

Approximately 2/3 of patients are cured of prostate cancer, but 1/3 will have recurrent disease within 10 years.

Following radical prostatectomy serum PSA is expected to be undetectable, or at the lowest level of detection by 4 weeks postoperatively.

In 2015 an estimated 220,800 new cases will be diagnosed and 27,540 are expected to die as a result of this disease, that is fewer than 12%.

The incidence of prostate cancer is likely to increase due to the aging population.

Of the 27,000 men destined to die of prostate cancer in 2007 the great majority were diagnosed before the age of 75 years, therefore PSA screening unlikely the benefit most men who have a low probability of surviving 10 years.

28,660 estimated prostate cancer deaths in 2008.

Prostate cancer is now the most frequently diagnosed of all new malignancies, making up about 25% of cases.

The annual incidence of prostate cancer is about 176 cases per 100,000 men per year.

Because of stage migration, the natural history of prostate cancer has shifted to a more indolent course in newly diagnosed patients.

Early diagnosis of prostate cancer by PSA produced a down stage migration at presentation.

Earlier diagnosis of prostate cancer has facilitated the increased use of aggressive local treatments such as radical prostatectomy and radiation therapy.

40% reduction in prostate cancer related mortality over the last two decades.

Lifetime risk 17%, whereas the lifetime risk of prostate cancer mortality is approximately 3%.

Most prevalent cancer among men in the U.S. with approximately 2.2 million men living with prostate cancer.

Five year survival for metastatic prostate cancer approximately 20-28%.

Survival for patients with castrate resistant prostate cancer is usually less than 3 years.

Incidence peaks at age 70-74 years.

European Randomized Study of Screening for Prostate Cancer demonstrated 20% mortality reduction from screening and treatment, however 48 additional men need to be treated to prevent one prostate cancer death (Andriole GL et al).

Prevention of one death from prostate cancer may require active treatment of up to 48 men and median follow-up of nine years and 12 men at a median follow-up of 14 years (Schroder FH et al, Hugosson J et al).

The majority of men diagnosed with PC are older than 65 years and had a low-intermediate risk disease, and more than 90% of these individuals will undergo active treatment that is unlikely to extend their lifespan, in contrast to younger patients or those with higher risk disease.

Localized prostate cancer and counts for about 93% of cases.

5-year survival for cancer localized to the prostate is nearly 100%.

Five-year survival rate for metastatic prostate cancer is around 30%.

Low risk patients are those with Gleason scores of six or less, PSA concentrations of 10 ng per mL or less or T1-T2a lesions and can be offered active surveillance.

Intermediate risk disease refers to Gleason score as of seven, PSA concentrations of 10-20 ng/mL or T2b-c.

Patients with intermediate risk prostate cancer have a nearly fourfold higher chance of dying of prostate cancer within 15 years compared to patients with low risk disease.

High risk or locally advanced prostate cancer refers to Gleason scores of eight or greater, PSA concentrations of greater than 20 ng/mL or T3/4 prostate cancer.

Mutations such as TP 53 loss, RB1 loss, or splice variants in the androgen receptor all have been linked to poor outcomes.

Prostate tumor cells can release atypical large extracellular vesicles that interact with the host site: known as oncosomes, they contain genetic material or proteins that are transferred to host organ cells.

Oncosomes released from prostate cancer cells interact with bone microenvironment and receptor activator of nuclear factor-kB (RANK), released from primary prostate tumor cells engage in a positive feedback loop with osteoblasts and osteoclasts that ultimately promote metastases to the bone.

Germline testing should be offering to all men with metastatic hormone sensitive prostate cancer with focus on genes that influence homologous recombination repair, such as BRCA1, BRCA2, and ATM.

Approximately 90% of men with metastatic castration resistant PC have molecular aberrations including: PIK3CA, RSPO, RAF, APC, Beta-catenin, and ZBTB16.

Approximately 2% of patients with PC express somatic gene alterations of MMR, indicating microsatellite instability.

High levels of androgen variant AR-V7 and high numbers of CTC’s are associated with poor prognosis.

Prostate cancer relies on androgen receptor signaling for growth throughout the disease continuum.

Approximately 15% of patients are diagnosed with high risk disease and 30-50% of these patients die from cancer

Unnecessary treatment of non-threatening PC disease is most common in older men.

Patients with neuroendocrine small cell prostate cancer variants have worst prognosis in patients with typical adenocarcinoma.

As many as 40% of prostate cancer patients are overtreated.

Mortality rate approximately 28 per 100,000 per year.

Among men younger than 65 years, sleeping only 3-5 hours per night significantly increases the risk of dying for prostate cancer.

During the previous decade cancer specific mortality rate for prostate cancer has been declining.

In the era of prostate-specific antigen screening up to 60% of patients diagnosed may not require therapy (Welch HG, Black WC).

Stage migration has occurred with the use of PSA such that the vast majority of patients with newly diagnosed prostate cancer have clinically localized disease, which is defined by the absence of nodal or distant metastases.

Only one in five men have true unilateral prostate cancer on template biopsies.

Patients with lymph node positive prostate cancer separated into two groups, mainly on the basis of the bulk of nodal disease: Patients with negative staging scans who have evidence of lymph node involvement at the time of pelvic lymph node dissection for radical prostatectomy, and a group of patients with pathologically node positive disease identified on scans and in whom surgery is rarely attempted.

There is no evidence available from randomized trial to guide appropriate use of local therapy for clinical node positive patients.

Recent retrospective studies have suggested both prostatectomy and radiation have improved cancer-specific survival and overall survival (Tward, Rusthoven, Engel).

Between 1990 and 2004 2.4% of patients with newly diagnosed with prostate cancer presented with bone metastases (CaPSURE registry).

Molecular subtyping includes the luminal and basal molecular classification with approximately 2/3 of patients with localized prostate cancer having luminal type and 1/3 in having basal types of types, with the suggestion that patients with luminal type may respond better to first line androgen deprivation therapy.

The Decipher prostate test is a genomic classifier with a 22 gene score that can predict the risk of prostate cancer metastases at initial diagnosis and after radical prostatectomy.

Prostate cancer with a luminal expression is associated with a high androgen receptor signaling and steroid hormone receptor processing and is observed more frequently in indolent and hormone sensitive disease.

Conversely prostate cancer with basal expression profiles associated with stem cell and epithelial-mesenchymal transition biology and MYC transcriptional programs shown to be enriched in aggressive castrate resistant disease.

Acinar-type adenocarcinoma is the most common malignancy of the prostate, accounting for more than 90% of malignant lesions.

Acinar-type adenocarcinoma typically involves the peripheral zones and is associated with high-grade prostatic intraepithelial neoplasia, which is the only recognized premalignant prostate lesion.

Other subtypes include small cell neuroendocrine cancer, adenoid cystic, basal cell, squamous cell, urothelial and sarcomatoid lesions may occur alone, but are more commonly associated with adenocarcinoma.

No single molecular event initiates prostate cancer but fusion chromosomal rearrangements with oncogenic transcription factor genes specific for this cancer have been implicated.

Recurrent gene fusions involving ETS family of transcription factors ERG and ETV1, and the 5’untranslated region of TMPRSS2 on chromosome 21 have been identified in 50-70% of malignant cells (Tomlins SA).

Estimated that 130,000 men per year are treated for cure by radical prostatectomy or radiation therapy.

The 10 year and 15 year relative survival rates for PC are 98% and 95%, respectively (ACS).

5-year survival for men diagnosed with local or regional disease was 61% in 1973, 74% in 1981 and 100% in 1995-2000 suggesting that the increased survival rates likely an artifact of PSA screening lead time bias.

Relative 5-yr survival rate for all stages is almost 100%, relative 10-yr survival rate is 99%,15-yr relative survival rate 94%.

The most common non-skin cancer in the U.S.

7th leading cause of death in the U.S.

Less than one third of patients with metastatic disease will be alive within 5 years of diagnosis.

Second most common cause of cancer related death in African-American men.

The mortality rate ratio between African-Americans and white men is higher for prostate cancer than any other malignant process.

African-American men present with higher stage, more aggressive disease and those of other racial/ethnic groups.

African-American men are more than six times as likely as whites to have adverse pathologic evaluation.

Race and ethnicity correlate with survival following a diagnosis of prostate cancer, in that blacks experience higher prostate cancer specific mortality compared to whites.

The incidence among Black men is 1.7 times as high as men as White men, and mortality is 2.1 times high.

The incidence and mortality are the lower among Hispanic men, and Asian men, than among White and Black men.

Prostate cancer in African American men transforms into advanced metastatic disease at a 4:1 ratio compared to white patients.

Men with low risk prostate cancer followed for a median of 7.6 years: African-American men compared with white men had a statistically significant increase ten-year cumulative  incidence of disease progression and definitive treatment, but not metastasis or prostate cancer specific mortality (DekaR).

In the United States the incidence rate of prostate cancer is about 180 in black men compared with about 100 in white men, while the mortality rate is about 40 in black men compared with about 18 in white men all in 100,000 persons.

8q24 variants that may partially explain increased prostate-cancer incidence among Black men.

Black men have 67% higher rate of diagnosis of prostate cancer and this percentage continues to rise.

Black men are more likely to be diagnosed with higher grades of prostate cancer presentation including a 2 to 3 times higher rate of mortality compared with European American men.

Observational data suggest prostate cancer may exhibit a biologically distinct, more aggressive behavior in blacks.

Single nucleotide polymorphism in numerous metabolic genes are linked with prostate cancer and blacks, but not in their European American counterparts.

Studies suggest a link between ambient air pollution as well as traffic related air pollution in prostate cancer risk.

No racial differences exist in the median progression free survival by race, as defined by PSA progression in patients with metastatic castration resistant prostate cancer (Halaby S).

Long-term metformin use is associated with a significantly lower risk of new onset prostate cancer and all cause mortality in patients with type two diabetes than sulfonylureas

Prostate cancer risk in African Americans is 4 times greater as BMI increases from <25 to 35.

Compared with European Americans, African American men have a 60% greater risk of developing prostate cancer and more than a two-fold greater risk of dying of the disease.

Outcomes for localized vs. advanced disease: 5 year relative survival rates of 100% vs. 31.7%.

Patients with metastatic prostate cancer have a poor prognosis and the predicted survival rate of fewer than 2 years from initial time of progression.

In 1980 lifetime risk of prostate cancer was 1 in 11 and today it is 1 in 6.

One in 6 men will be diagnosed with prostate cancer during their lifetime.

Lifetime rate of death from prostate cancer 3-4 percent.

Twin studies suggest up to 42% of risk explained by genetic factors.

40-45% of interindividual variability in PSA concentrations explained by genetic factors.

Associated with 100 single nucleotide polymorphisms and increased risk of prostate cancer.

Eight times as many men are diagnosed with prostate cancer each year as the number of men dying from it.

Death as a result of prostate cancer increases with increasing age, despite increasing death rates from other causes.

Patients 75 years or older represent over one fourth of prostate cancer cases, but they contribute more than half of deaths as a result of prostate cancer.

An adult male has a lifetime risk of diagnosis of 16.4%, and the lifetime risk of dying of only 2.7% (Alterkruse SF et al).

African American adult males have a lifetime risk of diagnosis of 19.6% and the lifetime risk of death of 4.7%.

Increase in the incidence over the last two decades related to use of prostatic specific antigen and the increasing rates are now reaching a plateau.

SLCO2B1 is an organic anionic transporter whose expression increases on progression from hormone sensitive to castrate resistant disease.

Patients AR-V7 variants do not respond to enzalutamide or abiratone.

Statins compete with dehydrepiandrosterone for influx by SLCO2 B1 which may decrease prostate cancer tumor’s available androgen pool.

Use of statins associated with the median ten-month prolongation in time to progression with androgen deprivation therapy and 17% reduction in hazard of progression during ADT therapy.

Microsatellite instability is found in approximately 3% of patients with metastatic castrate resistant prostate cancer and these patients have a 50% response rate to anti-PD-1 checkpoint inhibitor therapy.

There is a beneficial role of statin use after diagnosis across the continuum of prostate cancer.

In a meta-analysis of six studies, the use of statins was associated with a 24% lower risk of cancer mortality among patients with prostate cancer.

In studies of men with advanced prostate cancer, those who were taking a statin at the time of the initiation of androgen-deprivation therapy had a longer time to progression compared with nonusers of statins.

Larsen et al study included 31,790 men with prostate cancer, of whom 7,365 died of the disease, and reported a hazard ratio. for postdiagnostic statin use and prostate cancer mortality of 0.83.

A biologic mechanisms that underlie this association have been postulated as cholesterol being a precursor of androgens, and can act by reducing androgen bioavailability, thereby limiting tumor growth.

Cholesterol-independent pathways that mediate statin action in prostate cancer may also be operative.

Statins use transporters that interfere with androgen precursor cellular uptake by blocking solute carrier organic anionic transporters.

In African-American men, vitamin D deficiency was associated with increased odds of prostate cancer diagnosis on biopsy.

Severe vitamin D deficiency was positively associated with higher Gleason grade and tumor stage.

Vitamin D deficiency had a significant association with aggressive tumor characteristics in men with newly diagnosed prostate cancer.

A 25-hydroxyvitamin D (25-OH D) <12 ng/mL more than tripled the likelihood that the biopsy would reveal a high Gleason score and doubled the odds for a higher disease stage.

Among African-American men, low serum 25-OH D also increased the odds of prostate cancer diagnosis.

As compared with their European-American counterparts, African-American men have a 60% greater risk of developing prostate cancer and more than a twofold greater risk of dying of the disease.

Vitamin D deficiency has a higher prevalence in northern latitudes, older people, and African Americans.

Some evidence also has suggested an inverse association between prostate cancer and UV radiation exposure in the U.S.

African-American men with positive prostate biopsies had significantly lower mean 25-OH-D level where as non-African-American men did not.

Among European-American men tested, the investigators found no associations between vitamin D status and prostate cancer diagnosis.

There is an association between 25-OH-D level and Gleason grade on biopsy.

Men who were vitamin D deficient also were more likely to meet NCCN criteria for high risk and very high risk as opposed to low and intermediate risk.

The same analyses of African-American men showed a significant association between serum 25-OH-D <20 ng/mL and a positive prostate biopsy.

Up to 19% of men newly diagnosed with prostate cancer have very low risk disease which is defined as PSA < 10 ng/mL, PSA density of 0.15 nanograms per mill per centimeter3, Clinical stage T1c or less, Gleason score 6 or less, positive cores 2 or less, and cancer involvement per core less than 50%.

The positive predictive values of digital rectal exam and serum PSA value below 10 ng/mL is reported as less than 30% and 25-30%, respectively.

Treatment in older patients must be balanced saline relative life expectancy and consideration of the aggressivity of the cancer.

Only 12% of older men with prostate cancer are without comorbidities, disabilities, or geriatric syndromes.

Second leading cause of cancer death in men, but only 15% of patients diagnosed with PC will die from it.

Prostate cancer antigen (PCA3) gene located on a non-coding segment of mRNA, is prostate specific and over expressed in 95% of prostate cancers.

Median age at diagnosis 68 years in white men and 65 years in African American men in 2002.

Older age, African American race and family history are the three nonmodifiable risk factors

Modifiable lifestyle factors include diet, smoking, exercise and weight may affect risk.

Current smokers at the time of curative treatment for localized prostate cancer are at higher risk of experiencing biochemical recurrence, metastases, and cancer specific mortality.

Saturated fats are associated with higher risk of PC death.

Marine fatty acids and monounsaturated fat associated with the low risk of PC.

Total dietary consumption of fresh fruit and particularly citrus fruit is associated with a modestly lower risk of developing prostate cancer.

Among men with non-metastatic prostate cancer, replacing carbohydrates with animal fat with vegetable fat may reduce the risk of all-cause mortality (Richman EL et al).

In the above prospective analysis, vegetable fat intake after diagnosis of prostate cancer was associated with a lower risk of lethal prostate cancer and all cause mortality.

Obesity at time of diagnosis associated with increased risk of metastases and death.

The one factor clearly associated with aggressive prostate cancer is obesity, which often is a consequence of excessive intake of simple sugars.

Following definitive treatment with radiation for prostatectomy the highest risk of recurrence is within 5 years following treatment, although patients can be at risk for up to 10 years or more.

Long-Term Evidence Supports Use of SBRT in Prostate Cancer

Stereotactic body radiation therapy (SBRT) has been found to be a safe and effective option for patients with low- and intermediate-risk prostate cancer.

Conventional radiation therapy requires treatment daily, for an average duration of 9 weeks.

With SBRT patients can reduce their treatment course to approximately 4 or 5 days.

Using stereotactic body radiotherapy, which has a higher dose of radiation, can safely and effectively be done in a much shorter time frame without the additional toxicity or compromising any chance of a cure.

Results showed that the 7-year cumulative biochemical recurrence rate for men with low-risk disease was 4.5%, 8.6% for favorable intermediate-risk disease, and 14.9% for those with unfavorable intermediate-risk disease.

The biochemical recurrence rate for all patients with intermediate-risk disease was 10.2%.

The likelihood of metastasis following by a chemical recurrence on said is 37% have five years, signifying metastatic castrate sensitive prostate cancer development.

Obesity associated with poor prognostic factors such as high grade and non localized disease.

Prostate gland imaging for prostate cancer helps to assess tumor size, multifocality, extracapsular extension, seminal vesicles extension, neurovascular bundle involvement, bladder involvement, assessment of spread to lymph nodes and bones.

Imaging to provide intervention for prostate biopsy and can assess tumor therapeutic response.

MRI imaging is recommended before prostate biopsy.

MRI with targeted and standard biopsy in men with MRI results suggestive of prostate cancer was non-inferior to standard biopsy for detecting clinical significant prostate cancer and resulted in less detection of clinically insignificant cancer (STHLM3 consortium).

Transperineal biopsies are recommended rather than transrectal ultrasound guided biopsies.

When a multi parametric MRI is negative and clinical suspicion of prostate cancer is low, the biopsy can be omitted.

Patient with intermediate or high-risk disease should have imaging for nodal or metastatic disease.

Whole body MRI, PET imagery and PSA antigen pet/CT have better sensitivity and specificity than CT or  bone scan, but have not been shown to improve clinical outcomes.

Ultrasound is the most common imaging technique for direct visualization of the prostate and is essential for image guided prostate biopsies.

Ultrasound of the prostate is real-time imaging, portable, low-cost, and can visualize intraprostatic zonal anatomy.

Ultrasound of the prostate of the peripheral zone shows increased echogenicity compared with the central gland and prostate cancer presents as a hypoechoic area in the peripheral zone.

Prostate transrectal ultrasound is not very sensitive or specific for the detection of prostate cancer.

Prostate transrectal ultrasound has only limited accuracy for the detection of extraprostatic tumor involvement, and has no role in the evaluation of prostate cancer metastases.

MRI is currently the best imaging modality for prostate cancer and it usually involves scanning with T2 weighted diffusion weighted, and dynamic contrast-enhanced MRI.

MRI imaging has a sensitivity of 61% for detection of prostate cancer larger than 3 mm in size on T2-weighted images (Turkbey et al).

MRI increases the detection of clinically significant cancers by 30% compared with standard 12-coore biopsies.

MRI is widely used to help detect prostate cancer, especially in patients who have had previous negative biopsy with persistent elevated PSA levels.

Detection rate MRI guided target biopsy ranges between 11 and 54%.

Biochemical relapse by 10 years occurs in 20-40% of men, regardless of the type of therapy.

Most patients with biochemical relapse do not die of their disease, and approximately 55% survive 15 years.

Biochemical relapse defined as an initial serum PSA of 0.2 ng/mL, with a second confirmatory level of greater than 0.2 ng/mL (Cookson MS).

Recommended to have metastatic scanning once a biochemical relapse reaches 2 ng.

The initial postoperative PSA is measured 6-12 weeks after radiacal prostatectomy.

In a retrospective study of 358 pateints undergoing a radiacal prostatectomy it was found that when the PSA rose to greter than 0.2 ng/mL after surgery the 1 and 3 year risk of additional PSA progression were 86% and 100, respectively (Freedland SJ).

Biochemical relapse with increasing PSA is not necessarily associated with clinical disease progression.

Only one third of patients with biochemical relapse progress to metastatic disease (Pound CR).

Median time from biochemical relapse to death in patients treated with radical prostatectomy in a Hopkins study was 18 years (Pound CR).

Median time to clinical metastases after biochemical relapse is 2-3 years.

In a randomized study of 731 men with localized PC, mean age 67 years, PSA 7.8 ng to radical prostatectomy or observation: radical prostatectomy did not significantly reduce all-cause or PC mortality through 12 years of follow-up (Prostate Cancer Intervention versus Observation Trial (PIVOT).

In patients with high risk Gleason score of eight or greater at biopsy, there is suboptimal PSA control at five years following prostatectomy, and in the setting of uninvolved seminal vesicles or lymph nodes, the dominant pattern of failure is local, and therefore postoperative radiotherapy should be considered.

In a retrospective study of men with rising PSA level following prostatectomy, the median time from the first postoperative elevation in the PSA to the diagnosis of metastatic disease was eight years, and the higher Gleason score, a shorter interval from surgery to the first elevation in the PSA, a shorter doubling time of the PSA were associated with a shorter time to metastases. (Pound CR).

In a Mayo clinic study 73% of patients that had biochemical relapse after radical prostatectomy did so within 5 years of the procedure, and PSA doubling time <12 months was associated with an increased risk for clinical progression regardless of the interval from radical prostatectomy (Ward JF).

The PROTECT trial shows level I evidence that there is no difference in prostate cancer specific mortality among radical prostatectomy, radiation therapy, and active surveillance at 10 year follow-up for patients with low-risk Gleason score of 6 and Intermediate Gleason score 7 prostate cancer.

After 15 years of follow up, prostate cancer, specific mortality was low, regardless of the treatment is signed between monitoring, surgery, and radiotherapy for localized prostate cancer (ProtecT)

Prostate cancer specific death occurred in 3.1% of the active monitor group, 2.2% in the prostatectomy group, and 2.9% in the radio therapy group.

In the above study at the end of 15 years 24.4% of the patients in the active monitored group were alive without any prostate cancer treatment.

In a study of 189386 men age 50 – 69 who underwent a single PSA screen had their outcomes compared to 219439 controls: the proportion of men diagnosed with prostate cancer was higher in the screened population 4.3% versus 3.6% in the non screened group but no difference in prostate cancer mortality nor overall mortality after a median follow-up of 10 years (Martin RM).

Following radical prostatectomy serum PSA is expected to be undetectable, or at the lowest level of detection by 4 weeks postoperatively.

In a study of 623 US Veterans treated with radical prostatectomy or radiation therapy from 1991-1995 biochemical recurrence (PSA> 0.4 ng/mL) occurred 37-48% of patients over 15 years of follow-up (Uchio EM).

Randomized trial for treatment of intermediate risk prostate cancer is not inferior to standard RT (Catton CN).

In the above study, regardless of the primary treatment, a plateau in biochemical recurrence was observed at approximately 5 years after treatment, indicating that late failures are relatively uncommon: biochemical recurrence was associated with a higher mortality from prostatic cancer, but death from prostate cancer was seen in less than half of the patients with biochemical recurrence (Uchio EM).

Biochemical relapse in patients with organ defined disease after radical prostatectomy by PSA of 0.2 ng/ml or greater, followed by a confirmatory test with the same result.

Some patients have a low measurable PSA after radical prostatectomy which persists and does not reflect recurrent cancer.

Higher risk of biochemical recurrence of disease progression after radical prostatectomy.

Biochemical relapse after radiation is more difficult to define as PSA levels fluctuate and may take 12 to 24 months achieve a nadir level after completing the radiation.

Following radiation the majority of men achieve a PSA nadir of less than 1 ng per mL.

The rise of 0.2 ng/mL or more above the nadir following radiation suggests biochemical relapse.

PSA bounce refers to a transient increase in PSA following external beam radiation or brachytherapy and must be differentiated from biochemical relapse or local recurrence.

PSA bounce may be precipitated by ejaculation, proctitis or instrumentation (Roach M).

PSA bounce associated with 20% of cases of external beam radiation and brachytherapy, and more than 90% of cases occur within 12 to 26 months after treatment (Rosser CJ).

No standard definition for PSA bounce exists and therefore has a reported frequency of 12-84% (Caloglu, M).

Highest risk ethnic group is among African-Americans.

Mortality rate from prostate cancer among African Americans approximately twice that of white Americans.

Highest age standardized incidence in the U.S

Lower socioeconomic status associated with decreased survival rate in men with local or regional stage prostate cancer.

Median age at death due to prostate cancer is 78 years in white men and 76 years in African American men.

Mortality rates have declined in the last 10 years from approximately 40,000 deaths per year in the early 1990s to estimated 29,900 in 2004.

Risk factors include age, family history, African American race and possible dietary fat intake.

International incidence rates vary more than 65-fold from low-risk to high-risk populations.

Cumulative risk of prostate cancer in patients with Lynch syndrome is 2 fold higher than the general population.

Tomatoes and tomato based products, cruciferous vegetables, soy, legumes may be beneficial for prostate cancer.

Tomato sauce intake associated with a decreased risk of prostate cancer.

Vitamin E, selenium, omega 3-fatty acids, soy, polyphenols and isoflavones in the diet may be protective.

In the SELECT (Selenium and Vitamin E Cancer Prevention Trial) trial dietary supplementation with vitamin E significantly increased the risk of prostate cancer, 17%, among healthy men (Klein E et al).

Src genes overexpressed in prostate cancer and other malignancies.

Fyn is the most overexpressed Src family of protein kinases in prostate cancer, with increased expression with metastatic disease. And with the transition to castrate resistant disease.

The risk for developing aggressive, high-grade PC is 2.5 times greater in men with the highest percentages of docosahexaenoic (DHA)omega -3 fatty acid compared with those with the lowest levels of DHA (Fred Hurchison Cancer Research Center).

Men with the highest blood ratios of trans-fatty acids have a 50% reduction in the risk of high-grade PC (Fred Hutichison Cancer Reserach Center).

Milk and other dairy products, saturated fat, calcium high doses of zinc, grilled meats and heterocyclic amines may increased risk .

Daily use of aspirin and NSAIDs associated with reduced risk.

Regular aspirin intake may reduce risk of death from prostate cancer.

Substantially higher incidence in African American men compared to aged-matched white American men.

Migrant population studies show that men who move from low-incidence to higher-incidence countries experience a shift in risk toward that of men from the higher-risk areas, implying a role of environmental factors in the development of this disease.

Arises and develops mainly in the peripheral zone of the prostate.

The presence of prostate cancer in the fibroadipose tissue surrounding the prostate is referred to as extraprostatic extension.

50% of men with prostate cancer die of other causes, especially cardiovascular disease.

Expectant management is applicable for patients who are potentially curable.

Expectant management at minimum, involves monitoring every 6 to 12 months with a PSA and DRE.

Expectant management of prostate cancer may include surveillance, prostate biopsies, at intervals of 12 to 18 months, at some centers and others incorporate periodic imaging studies.

Active surveillance is the preferred option for very low risk patients with life expectancies of less than 20 years as it reduces overtreatment of indolent cancers while allowing for curative intervention if disease progression is detected.

Is Active Surveillance for Prostate Cancer Safe?

Only a fraction of men who chose active surveillance (AS) instead of immediate treatment for early stage prostate cancer actually undergo monitoring as recommended.

Guidelines established by the National Comprehensive Cancer Network (NCCN) recommend that men undergoing surveillance for low- to intermediate-risk prostate cancer need to have their prostatic specific antigen (PSA) levels tested at least once every 6 months, have an annual digital rectal exam (DRE), and a repeat biopsy of the prostate within 18 months of their initial diagnosis.

There is some evidence from clinical trials to suggest that surveillance may not be as effective as immediate treatment if patients are not well monitored.

In the ProtecT trial, no differences in prostate cancer-specific mortality between immediate treatment groups and those assigned to surveillance.

The incidence of disease progression and metastases in the surgery and radiotherapy arms was lower at a median follow-up of 10 years in the immediate treatment group than in the active surveillance arm.

The standard treatment for patients with biochemical recurrence after radical prostatectomy is salvage radio therapy: compared with  no salvage therapy, salvage radiotherapy significantly reduces the risk of distant metastasis and allows postponement of long-term androgen deprivation therapy and related side effects.

Salvage radiation therapy is associated with a favorable outcome: five-year progression free survival is 68%  In patients  with persistent to rising PSA after Prostatectomy and 87% among patients  with PSA concentration less than 0.3 ng/mL at the time of biological recurrence,70% among those with PSA concentration of 0.3-0.7 ng per mL and 47% among those with PSA concentration greater than  0.7 mg/dL.

Salvage radiotherapy at five years shows metastasis free survival at 92.5%, prostate cancer specific survival 96.4% and overall survival of 94.5%.

Older patients with low risk disease or short life expectancy due to advanced age, poor health status, significant comorbidities, most likely to benefit from active surveillance.

Expectant management of prostate cancer should define criteria for interventional care, such as local progression, perineural invasion, progressive Gleason score, and PSA kinetics.

Perineural invasion (PNI) is found in approximately 30% of prostate cancer biopsies.

PNI means that the pathologist has seen prostate cancer cells surrounding or tracking along a nerve fiber within the prostate.

Neurons within the prostate travel outside of the gland through microscopic holes within the prostate capsule.

The prostate capsule serves as a barrier preventing the spread of cancer outside of the prostate, but because nerves travel through holes in the capsule perineural invasion (PNI) may allow spread.

Men with PNI have a 2-3 times higher rate of extracapsular extension and nearly twice the likelihood of positive margins after prostatectomy when compared to men without PNI on their prostate biopsy.

The presence of PNI at least doubles the chance of T3 disease in a man undergoing treatment for what is clinically localized, T2 disease.

PNI on biopsy is associated with higher grade disease (Gleason 8-10) on final pathology even when only low grade disease (Gleason <7) is found on biopsy.

Studies have demonstrated that more than 40% of men with PNI and low grade disease on biopsy are subsequently found to have high grade disease on final pathology after prostatectomy.

Studies demonstrate a higher risk of seminal vesicle invasion and lymph node metastases in men found to have PNI.

PNI has has been demonstrated to negatively affect prognosis after radical prostatectomy surgery: men with PNI on biopsy were found to have three times the likelihood of PSA recurrence as compared to those men without PNI.

Men with low risk prostate cancer (Gleason 6, T1-T2a, and PSA<1O) and PNI are three times more likely to require salvage radiation than their low risk counterparts without PNI.

The prognosis after radiation therapy appears to be negatively impacted by the presence of PNI.

Studies have shown removing the nerves on the side of the prostate with PNI on biopsy led to a positive margin rate of 11%.

The positive margin rate is 100% when the nerves were spared on the side of PNI.

Presently, most urologists will sacrifice nerve sparing in order to assure negative margins in men with PNI.

Given the high likelihood of positive margins and T3 disease, patients with PNI on biopsy likely need to undergo radiation therapy following radical prostatectomy.

Radiation oncologists approach patients with PNI as high risk patients regardless of clinical stage, PSA, or Gleason score. and often treat men with PNI with a combination of radiation and hormonal therapy rather than radiation therapy alone, and may also use dose escalation as part of their radiation protocol.

Among surveillance studies on low risk patients the chance of progression by grade by subsequent biopsy is 2.5-28% and ten-year disease specific survival is 97-100 percent (DallEra MA et al).

In the United States for diagnosis of prostate cancer almost invariably is associated with treatment, surveillance has been reported only to be between 3-8%.

Active surveillance is dynamic and involves frequent evaluations of prostate cancer and overall health of the patient to determine if treatment should be initiated.

Androgen deprivation therapy (ADT) for most men with localized PC who defer surgery or radiation, primay ADT offers no mortality benefit (Potosky AL et al).

In the above retrospective cohort study looking at 15,170 men with newly diagnosed, clinically localized prostate cancer: There was no difference between primary ADT and untreated patients all cause mortality.

In the Scandinavian prostate cancer group study number for the randomized trial of radical prostatectomy versus watchful waiting in men with localized prostate cancer, diagnosed before PSA testing showed a survival benefit of radical prostatectomy is compared with observation at 15 years.

Am update of the above study with 23.2 years of follow-up confirmed a substantial reduction in mortality after radical prostatectomy versus watchful waiting.

Watchful waiting we delayed hormone therapy for symptomatic progression is an option for men who are not suitable for, or unwilling to have, treatment with curative intent

In the prostate cancer intervention versus observation trial (PIVOT), initiated in the early PSA era, showedk that radical prostatectomy did not significantly reduce prostate cancer specific or overall mortality after 12 years.

In Europe active surveillance occurs following diagnosis in 25-40% of patients.

Expectant management, known as active surveillance, considers the possibility that the malignancy is indolent, such that treatment can be deferred to possibly avoided.

In short-term studies active surveillance has demonstrated a low risk of prostate cancer specific mortality.

Gleason score 6 or less refers to low grade prostate cancer.

In a study of 241 men localized prostate cancer (T1c) and an initial Gleason score of 6 or less observed for approximately 3 years: Grade progression occurred and 19% of men, and more than one a half were within 2 years of diagnosis (Sheridan TB et al).

For patients managed with expectant care the PSA and digital rectal exam are required every three months for 2 years.

With expectant management the patient should be rebiopsied at three months or 1 year, or both.

With expectant management if the disease is stable for 2 years frequency of follow-up can be relaxed to 6 months-1 year.

With expectant management active treatment should begin if the PSA doubled in less than 3 years, an abnormal rectal exam manifested, or progression to a higher Gleason system score occurred.

Expectant management acceptable results have been obtained with observational periods up to 10 years (Klotz).

In a study of 769 men with PC prospectively on active surveillance: very low risk of cancers clinically staged T1C, PSA density less than 0.15 ng per mL, and Gleason score 6 or less, two or fewer cores with cancer- the median survival free of intervention was 6.5 years after diagnosis and the proportions of men remaining free of intervention after two, five, and 10 years of follow-up were 81%, 59%, and 41%, respectively (Tosoian JJ et al).

In men with favorable risk disease active surveillance has been associated with a prostate cancer-specific mortality of less than 3% at 10 years (Klotz L et al).

The risk of death within 15 years is estimated to be 4 to 30 percent, depending upon the age of the patient at diagnosis, the grade of the tumor.

Prostate cancer patients with PSA levels > 20 ng/ml are classified as having high-risk disease when considering primary therapy.

In a retrospective analysis of radical prostatectomy of 712 patients European database with a baseline PSA level > 20 ng/ml: Group A: Patients with a preoperative PSA level >100 ng/ml, Group B: Patients with a preoperative PSA level between 50.1 and 100 ng/ml , Group C: Patients with a preoperative PSA level between 20.1 and 50 ng/ml-10-year projected prostate cancer-specific survival appeared to be significantly affected by the baseline PSA level with 79.8 percent in Group A, 85.4 percent in Group B, 90.9 percent in Group C, 10-year projected overall survival was apparently not significantly affected by the baseline PSA level, 59.6 percent in Group A, 71.8 percent in Group B,75.3 percent in Group C, and at a median follow-up of 78.7 months, rates of biochemical progression-free survival were, 6.6 percent in Group A, 8.3 percent in Group B, 25.8 percent in Group C. (Gontero et al).

In the above study the authors conclude that 10-year prostate cancer-specific survival is high even among men with baseline PSA levels >100 ng/ml, and that radical prostatectomy may be an appropriate treatment option even for some men whose baseline PSA level is >100 ng/ml.

In a study of 2500 men with clinically localized disease treated with radical prostatectomy and overall 15 year actuarial recurrence rate of 66% for biochemical, local or distant recurrences (Nam K).

In an analysis of 5000 patients with stage TI-T2 prostate cancer treated with definitive external beam radiation, the biochemical disease-free survival rate was 69% after 5 years in 53% after 8 years (Kuban DA).

In patients with localized prostate cancer functional impairment associated with management attenuated by five years: men undergoing prostatectomy has worse incontinence at five years and worse sexual function at five years compared with men who had brachytherapy or external beam radiation (Hoffman KE).

Most men die with rather than from prostate cancer.

Interpatient molecular heterogeneity of disease.

Men with low-grade disease rarely develop detectable metastases within 10 years of diagnosis.

Doubling times may exceed 4 years in patients with low-grade disease.

Ki-67 positivity is strongly associated with pathologic stage, Gleason score, tumor volume, and nodal status in prostate cancer.

In prostate cancer tumors with more than 5% of cells positive for Ki-67 are significantly more likely to have biochemical failure within 10 years of surgery (Tollefson MK).

Men with prostate cancer and more than 5% of cells positive for Ki-67 are more likely to suffer systemic progression or cancer specific death during a 10 year followup.

The predictive value of Ki-67 was a better predictor of outcome then preoperative PSA, clinical stage or Gleason’s score for prostate cancer(Tollefson MK).

Metastatic castration resistant prostate cancer have genomic aberrations that interfere with DNA repair.

Patients with gene alterations associated with DNA repair such as BRCA2, or tumor suppressor genes TP53, RB1 and PTEN can have worse outcomes.

Germline or somatic DNA damage response (DDR) alterations occur in 23–27% of men with prostate cancer, and are associated with worse outcomes.

A minimum of 10-15 years of follow-up is desirable to provide a complete picture of prognosis.

Patients with nonmetastatic hormonally refractory prostate cancer have a median survival of 68 months, whereas patients with bone metastases have a median survival of only 40 months.

Bone metastases is a sentinel event requiring more aggressive therapy and indicates more worsening prognosis.

Testicular atrophy at the time of therapeutic orchidectomy is associated with poor prognosis.

Bone is the most common site in metastases and effects 85-90% of men with advanced disease.

Approximately two thirds of patients have bone metastases at autopsy, and over 90% of patients with metastatic castration resistant disease have evidence of osseous metastases S.

Bone metastases are major cause of morbidity and mortality, with nearly all men with fatal prostate cancer have such metastases and, for the most of these men, it is the dominant or only site of metastases.

Androgen deprivation is the backbone of treatment for advanced prostate cancer but ultimately all patients develop disease progression even with castrate levels of testosterone.

Long term androgenic deprivation hormone therapy with locally advanced prostate cancer associated with decreased local failures and distant metastases, improved biochemical control and improved absolute survival compared to hormonal treatment given at the time of recurrent disease.

A meta-analysis of randomized trials indicates that adjuvant hormonal therapy is associated with a 30% reduction in prostate cancer mortality.

Presently several agents are added  upfront to androgen deprivation therapy, and include: docetaxel , abiraterone, Apalutamide, enzalutamide, and darolutamide.

This added approach is called treatment intensification, and these combinations of drugs lead to better overall survival, than  ADT alone.

Practice guidelines for the treatment of metastatic castrate sensitive prostate cancer has changed from monotherapy with ADT to treatment intensification as the standard of care.

Estrogens effective treatment in prostate cancer but has more adverse cardiovascular risks than other approved hormonal treatments.

Tumor volume predictor of tumor recurrence.

With tumor volume less than 3.0 cm3 pelvic lymph nodes are cancer free.

More than 85% of patients with tumor volume less than 2cm3 remain free of disease.

In patients with tumor volume of 7 cm3 or greater tumor progression will occur in 85% of cases.

Patients with tumors with volume less than 0.5-1.0 cm3 rarely progress.

pT3, extension beyond the capsule, has a risk of local recurrence and progression varies from 20-70% (Swindle).

Gleason score, initial PSA levels and positive seminal vesicles and positive surgical margins are independent predictors of biochemical progression.

Randomized studies for pT3 or pT2 disease revealed that adjuvant radiation after radical prostatectomy reduces risk of local relapse and biochemical progression by approximately 20% at 5 years (Bolla,M, Thompson IM).

Adjuvant radiotherapy after radical prostatectomy in patients with pT3mN0 tumors randomly assigned to wait and see therapy or radiation revealed higher biochemical progression free survival after 5 years with undetectable PSA (Wiegel T).

Adjuvant radiation for prostate cancer shows an advantage in freedom from biochemical failure for immediate postoperative radiation rather than for salvage radiation in the above study, and in a second study with longer follow-up indicated a reduction in clinical failure (Bolla M et al), and a third study with more than 15 years of follow-up showed improvement in survival rates ( Thompson IM et al).

Adjuvant radiation for prostate cancer for patients with stage pT3 disease, to prevent one death at 10 years, 12 patients will needed to be treated.

High-dose radiotherapy does not improve survival for men with intermediate-risk prostate cancer but does improve biochemical control and rates of distant metastases, when compared to standard radiotherapy.

Men who receive higher-dose radiotherapy undergo fewer salvage therapies to control tumors that had grown larger or had spread to another body site; however, they also experienced more side effects than did men on the standard radiotherapy treatment arm.

Radical prostatectomy reduces prostate cancer mortality and the risk of metastases when compared to watchful waiting in patients in whom prostate cancers diagnosed without PSA screening(Bill-Axelson A).

Watchful waiting refers to no additional cancer evaluation or therapy in a patient with prostate cancer until local or systemic symptoms are present, thus excluding the concept of delayed intervention with curative potential.

Watchful waiting usually recommended in elderly patients with low-risk cancers or those with significant comorbidities.

Wiegel study a German Cancer Society demonstrated that patients who achieved an undetectable PSA after radical prostatectomy do profit from adjuvant radiation therapy.

Testicular atrophy at the time of therapeutic orchidectomy is associated with poor prognosis.

In peripheral and transition zone tumors smaller than 4 cm3 in volume the tumor remains confined to the zone but with larger tumor volumes bilateral prostate spread is more frequent.

Men with low testosterone levels have a much worse prognosis during subsequent chemical androgen ablation therapy.

Risk of bone fractures in 50,613 prostate cancer patients correlates with the use of gonadotropin-releasing hormone agonist therapy: at 5 years risks of fracture 12.6% for men who received no GnRH agonist therapy and 19.4% for men who did (SEER), and the rate of fractures requiring hospitalization was double in the ADT group compared to those who did not.

The Gleason system is the standard grading system in the U.S.

DAmico risk stratification categories patients as low (Gleason 6 or less, PSA 10 ng/mL or less and stage T2a or less), intermediate (Gleason 7, PSA 10-20 ng/mL and or stage T2b) and high risk (Gleason 8-10, PS greater than 20 ng/mL and or stage T2c or higher.

Prostate cancer-percent positive biopsies identified as an independent predictor of biochemical outcome.

Only 52% of patients with clinical organ-confined carcinomas are actually pathologically organ-confined at the time of radical prostatectomy.

96% of patients with extraprostatic extension have disease within 2.5 mm of the outer margin of the prostate capsule.

Newly diagnosed and untreated prostate cancer patients should undergo bone scan if there is bone pain, or elevated alkaline phosphatase.

From 70-80% of patients with metastatic prostate cancer have disease limited to bone.

More than 90% of patients with metastatic prostate cancer developed bone metastases.

The routine use of bone scan when the PSA is <20 ng/mL is to be discouraged.

Hormonal therapy results in tumor regression in the large majority of patients and reduces the PSA by over 95% in 90-99% of patients.

Use of second-line hormonal therapy is associated with lower response rates and no documented survival advantage.

Local recurrence incidence increases with pathologic Stage C disease, extracapsular extension and involvement of the seminal vesicles by tumor.

Involvement of the seminal vesicles is associated with a high-incidence of local tumor recurrence, distant metastases and decreased survival.

MRI and CT scans to evaluate lymph node metastases in the pelvis have low sensitivity of 0-30% for prostate cancer.

Lymph node size does not correlate with the presence of metastases, with one study 74% of metastatic nodes had an axial length <1cm and 8% of negative nodes had an axial length >1.5 cm (Tiquert R).

MRI and CT scan criteria for diagnosing lymph node metastases are not adequate and better imaging techniques are needed.

Choline C 11 Injection, a Positron Emission Tomography (PET) imaging agent used to help detect recurrent prostate cancer.

Choline C 11 Injection must be produced in a specialized facility and administered to patients shortly after its production.

NCCN guideline suggest patients with metastases to lymph nodes identified by imaging studies should be treated systematically wiith androgen deprivation, or radiation therapy with long-term androgen deprivation therapy (ADT) and patients with involved lymph nodes detected at the time of radical prostatectomy should be offered observation, ADT or radiation with long-term ADT.

Adjuvant radiotherapy improves local control but does not increase survival in patients with pathologic stage T3/4.

In a trial of radiation plus permanent androgen deprivation therapy with T1-T4 disease there was a survival benefit of 53% for the combination treatment vs. 38% in patients treated with radiation alone at 10 years.

Among patients with locally advanced disease phase 3 trials showed that when androgen deprivation treatment added to radiotherapy long-term treatment, of two years or greater, improved overall survival but also increases erectile dysfunction and the rate of myocardial infarction.

The combination of androgen deprivation therapy with radiotherapy improves outcomes, including survival in patients with high-risk localized prostate cancer compared with radiotherapy alone.

The combination of androgen deprivation therapy and radiotherapy is superior to androgen deprivation therapy alone and 3 years of androgen deprivation therapy is superior to 6 months in patients with higher risk prostate cancer.

Among patients with stage T1b, T1c, or T2a or T2b prostate cancer and a PSA level of 20 ng per millimeter or less, the short term use of androgen deprivation therapy four months before and during radiotherapy is associated with significant decreased disease specific mortality and increased overall survival – the benefit is seen mainly in intermediate risk, but not low risk men (Jones CU et al).

In the above study short-term androgen deprivation therapy conferred a increase in the 10 year rate of overall survival from 57 to 62%, and reduced the 10 year specific disease mortality from 8% to 4%, with reductions in biochemical failure, distant metastases, and the rate of positive findings on repeat prostate biopsy at two years.

Short-term androgen deprivation therapy (phase 3 clinical trials) for four months before and during radiation significantly improves local control and disease free survival among patients with bulky stage to T2c-T4 tumors.

Randomized studies reveal an overall cancer specific survival advantage when androgen suppression therapy is added to external beam radiation compared to radiation alone in treating patients with unfavorable localized disease or with locally advanced prostate cancer.

Androgen deprivation therapy-RTOG 92-02 study of 1554 patients with locally advanced prostate cancer (T2c-T4N0-X and PSA less than 150 ng/mL treated with combined androgen blockade for 2 months before and 2 months after radiation therapy of 65-70 Gy, with subsequent randomization of monthly ADT for 2 additional years or no further treatment-resulted in an absolute 10% improvement in disease free survival, from 40 to 50%, in patients with extended ADT therapy, at 5 years.

10 year analysis of the RTOG 92-02 study revealed disease free survival higher for patients receiving 2 additional years of ADT 22.5% vs. 13.2%, while the overall survival was similar at 53.9% vs. 51.6%.

The addition of 6 months of androgen suppression therapy to external radiation therapy increases overall survival in localized but unfavorable risk prostate cancer (D’Amico).

Short-term ADT improves radiation salvage after prostatectomy

Adding short-term androgen deprivation therapy (ADT) to radiotherapy as salvage treatment after radical prostatectomy was associated with significantly better metastasis-free survival at nearly 10 years compared with salvage radiation alone, long-term results of a randomized phase 3 trial show.

After a median follow-up of 9.3 years, the metastasis-free survival (MFS) rate for patients assigned to receive salvage radiation and short-term goserelin was 75%, compared with 69% for patients randomized to radiation alone.

There was no significant difference, however, in the secondary endpoint of overall survival at 10 years.

The patients were randomly assigned to receive standard salvage radiotherapy either alone or with hormonal therapy.

Progression-free survival (PFS), the primary endpoint, was significantly better with the combination than with radiation alone for both low-risk patients and high-risk patients.

Metastasis-free survival was also significantly better in the combination arm.

Biochemical control is improved, with testosterone suppression alone, making the conclusion that the combination therapy is more advantageous,

More than 80% of prostate cancer patients develop erectile dysfunction as a result of surgery or external beam radiation therapy.

Approximately one-third of patients who undergo prostatectomy will have positive surgical margins.

Recent surgical series with selected patients with clinical stage T3 have survival rates of with 5 and 10 year prostate cancer specific survival rates around 85-99% and 72-92%, respectively.

Of patients treated with prostatectomy for T3a disease those that develop a PSA recurrence with have a PSA doubling time of ? 9 months in nearly 50% and ? 15 months in 33% of patients.

At 15 years after radical prostatectomy for selected patients with T3a disease only 16% of patients die from prostate cancer.

Serum PSA levels increase two decades before the clinical detection of cancer, indicating that early cancers begin when the PSA is below 0.5 ng per milliliter.

Only 15% of stage T1a untreated patients progress to clinical disease.

Stage III (T3N0M0) locally advanced disease 50%-60% have microscopic evidence of extraprostatic disease.

Metastasizes to supraclavicular lymph nodes in fewer than 1% of patients.

Measurements of PSA indicate persistent or recurrent tumor in up to 27-53% of patients treated for localized prostate cancer by curative potential of surgery or radiation therapy.

Approximately half of patients with clinical stage T3a disease after surgery will have not developed PSA recurrence at 15 years.

Patients with localized disease treated with radical prostatectomy 35% will have recurrent disease by 10 years.

With biochemical recurrence after radical prostatectomy 37% will develop clinical evidence of metastatic disease and 57% will die of prostate cancer within 5 years.

Biochemical recurrence defined as 3 consecutive increases in PSA level after external beam radiation.

Daily consumption of a supplement containing soy protein isolate for 2 years after radical prostatectomy does not reduce biochemical recurrence of prostate cancer in men at high risk of PSA failure(Bosland MC et al).

Majority of patients with positive lymph nodes exhibit disease progression by 5 years.

99% of prostate cancers can be diagnosed at the localized and potentially curable stage by screening.

Disease specific 10-year survival following radical prostatectomy is about 85% and ranges from 94% for men with well differentiated cancer to 67% for men with poorly differentiated disease.

Bolla found the combination of hormonal therapy plus external beam radiation form locally advanced disease with a 5-year survival rate of 94% compared with 79% for men treated with radiation alone.

External beam radiation has a 10-year disease specific survival of 76% and ranges from 90% for well differentiated to 53% for poorly differentiated prostate cancer.

External beam radiation in low-risk patients with a PSA of 10 ng/ml or less, a Gleason score of 6 or less and a clinically staged T1c or T2a result in a less than a 2% a decade prostate-cancer specific mortality, whereas in patients with higher PSA levels or Gleason scores the estimated range is from 12-30%.

Prostate cancer-70 Gy external radiation is the standard dose at this time.

External beam radiation planning includes an approximate 5 mm safety zone around the prostate to account for subclinical extension of disease.

External beam radiation conventionally 70.2 Gy.

High dose conformed radiation rather than conventional dose external beam radiation for clinically localized prostate cancer results in fewer patients with increased PSA level 5 years after treatment and less likely to have locally persistent disease.

Randomized control study of patients with T1b through T2b localized prostate cancer with PSA levels less than 15 ng/mL to receive 70.2 Gy by external beam radiation vs. 79.2 Gy by conformal high dose radiation treatment resulted in 61.4% of men free of biochemical failure in the conventional group and 80.4% in the high dose group, i.e., a 49% reduction in the risk of failure at a median follow-up of 5.5years.

High dose conformal radiation 79.2 Gy.

RTOG 94-08 study 1,979 patients with T1b, to T2B prostate ca and a PSA level of 20 ng or lower randomized to hormonal therapy two months prior to and two months during radiation , or radiation alone: 51% of patients with hormonal therapy plus RT and 46% of patients with RT alone were alive at 12 years-indicating that patients with intermediate risk prostate cancer should receive adjuvant hormonal therapy (Jones CU)

In the above study short-term hormonal therapy given prior to and during RT increased chance of living compared to RT alone from 57% to 62% and increased the 10 year disease specific survival rate from 92% to 96% (Jones CU).

At two years following treatment 843 men underwent repeat prostate biopsy in the above study and those treated with hormonal therapy and RT showed no cancer in 78% of biopsies while the RT group alone only 60% were cancer free (Jones CU).

In the above study men with low-risk prostate cancer, hormonal therapy did not provide benefit.

Patients ideally suited for brachytherapy have a PSA<10, Gleason score <6 and stage T2a or lower.

Increasing radiation dose in localized prostate carcinoma undisputedly lowers the rate of biochemical recurrence and probably distal metastases as well.

Partin nomogram estmates the likelihood of organ confined disease based on preoperative PSA, clinical stage and clinical disease and Gleason score in men treated with radical prostatectomy in a cohort of 5730 men (Partin AW).

Brachytherapy treatment only group 10-year disease free survival 66%, while patients treatment with the addition of external pelvic radiation achieve a disease free survival of 79%.

Involvement of seminal vesicle implies poor prognosis.

DES 1 mg per day improves 5-year survival of metastatic prostate cancer from 50% to 30% compared to placebo.

Orchidectomy with DES is better than orchidectomy alone and equal to DES alone in slowing prostate cancer progression.

The probability of a positive bone scan is less than 5% until total PSA is increased between 40 and 45 ng/mL.

After detection of an elevated PSA following a prostatectomy men develop clinically apparent metastases after a median of 8 years and die after a median of another 5 years.

Patients with Gleason score of <8 have a 73% chance of remaining free of disease at 5 years compared to a 40% probability for men with higher Gleason scores.

Tumor volume highly correlated with capsular penetration, positive surgical margins, seminal vesicle invasion and PSA.

With androgen ablation disease progression occurs in approximately 50% of patients within 12 the 18 months after the initiation of treatment.

DNA aneuploidy and a high proliferation index are related in prostate cancer.

In the bone microenvironment prostate cancer cells secrete growth factors that induce stromal cell and osteoblasts to express RANKL an essential mediator of osteoclast formation, function, and survival. It’s him

Activation of osteoclasts by RANKL increases bone turnover, releases growth factors from bone matrix, and may promote establishment of PC in the skeletal.

High levels of RANKL (receptor activator of NF-?B ligand), its receptor (RANK), and protein osteoprotegerin (OPG) in prostatic cancer tissue than in normal prostate tissue.

Expression of RANKL, RANK and OPG correlates with Gleason score, tumor stage, tumor grade.

Alterations in PTEN common with loss of protein expression occurring in >50% of advanced prostate tumors.

Serum PSA levels and androgen receptor status, suggesting they are involved with growth of prostate cancer and bone metastases.

The use of three-dimensional conformal radiation techniques results in improved biochemical and clinical outcomes compared with conventional radiation treatment techniques for the treatment of clinically localized prostate cancer.

Patients with newly diagnosed prostate cancer do not require a bone scan if PSA < 20 ng/mL.

Approximately 1/3 of patients develop biochemical relapse after surgery or radiation.

Following biochemical recurrence, the median time to the development of metastatic disease is approximately 8-10 years.

NCCN guidelines: Stage I PSA declines of greater than 50% correlate with improved survival in patients treatment with second-line hormones or chemotherapy.

Abiratone a highly selective CYP17 inhibitor more than 10 times more potent than Ketoconazole.

CYP17 enzyme is key to the generation of androgens and estrogens in tumor tissue and adrenal glands.

Royal Marsden trial phase I study of Abiraterone in hormonal resistant chemotherapy na�ve prostate cancer patients associated with significant tumor activity.

The sequence of abiraterone plus prednisone followed by ((enzalutamide))9 has a significantly longer and deeper response to second line therapy than those who received enzalutamide followed by abiraterone plus prednisone in a phase 2 randomized controlled study.

A phase II COU-AA-004 trial of Abiraterone in patients with metastatic hormonally refractive patients after failure of ((Docetaxel)) based chemotherapy: at 3 months 45% of patients experienced a 50% decline in PSA.

A phase 3 trial COU-AA-301 trial involved a 2:1 randomization of men with metastatic castration resistant prostate cancer previously treated with docetaxel with abiraterone with 5 mg prednisone b.i.d. or placebo with prednisone 5 mg bid: Abiraterone significantly prolonged overall survival compared with placebo, 14.8 10.9 months.

In the CHAARTED study it was shown that combining ADT with docetaxel in men with hormone-naIve metastatic prostate cancer (mHSPC) yielded a remarkable overall survival benefit of 13.6 months as compared with ADT alone.

Neoadjuvant systemic hormonal therapy before radical prostatectomy in high risk patients does not increase surgical morbidity (Williams SB et al).

In the study of 56 men with localized high-risk prostate cancer defined as Gleason score = or > than eight, PSA = or > 20 mg/mL, T3 or T4 bulky disease, a high PSA velocity score, slightly more than one-third of patients had lymph node involvement: patients were treated with either 3-6 months of preoperative leuprolide or abiraterone, leuprolide and low-dose prednisone and then had biopsy of the prostate: a pathological complete response was observed in 10% of those treated with six months of combination therapy versus 4% in those with three months of combination therapy and near pathologic complete response was 24% versus 11%, respectively.

The above study suggests neoadjuvant therapy can make cancer disappear in a percentage of high-risk patients.

In the STAMPEDE and Latitude trials the addition of abiratone and prednisone to androgen deprivation therapy for newly diagnosed metastatic castration resistant prostate cancer patients reducing risk of death by nearly 40%.

In the STAMPEDE trial 2,000 men with advanced PC starting first line hormonal therapy and docetaxel for 6 weekly cycles with 10 mg prednisone.

In the above study docetaxel extended survival by .89 years for patients with metastatic disease and 0.78 years without metastatic disease.

Abiraterone was tested later in the STAMPEDE study indicating its benefits.

In the STAMPEDE  study arm H, added radiation to patients with low volume metastatic disease with minimal associated toxicity and decreased doses of 55Gy in 20 fractions administered to the prostate.

Mitoxantrone plus prednisone is superior to prednisone alone for palliation of symptoms in CRPC, 29% versus 12% without a difference in overall survival (Tannock IF et al).

TAX327 study randomized 1006 men with metastatic CRPC to receive docetaxel or mitoxantrone: significant benefits survival for docetaxel (Tannock IF et al).

Metastatic prostate cancer that is resistant to docetaxel associated with a median survival of 18 months.

Abiraterone, is a CYP17 inhibitor and when used with prednisone compared to placebo plus prednisone in men with metastatic castration resistant prostate cancer who had disease progression after docetaxel chemotherapy: was associated with a 35% reduction in the risk of death, with a median survival of 14.8 months versus 10.9 months among patients who received placebo plus prednisone.

Abiratone resulted in an improved prostate specific antigen response, and improved objective response on the bases of radiographic findings, longer time to disease progression, and a longer progression free survival on the basis of radiographic findings.

Enzalutamide demonstrated a high PSA response, with PSA reductions of at least 50% in 54% of patients and at least 90% in 25% of patients of refractory patients.

Adding enzalutamide to the current standard of care may significantly improve overall survival (OS) in men with metastatic hormone-sensitive prostate cancer (HSPC) according to an interim analysis of the international randomized phase III ENZAMET study.

Researchers found that 80% of men with metastatic HSPC who received this nonsteroidal anti-androgen drug along with the standard-of-care treatment were alive after 3 years compared with 72% of men who received other nonsteroidal anti-androgen drugs along with standard treatment.

Enzalutamide is a more effective inhibitor of the androgen receptor compared with bicalutamide, nilutamide, or flutamide.

Enzalutamide retains clinical activity as this second line drug following abiraterone, where as a very abireraterone retains no second line activity following enzalutamide

When added to testosterone suppression increases overall survival in patients with high and low volume of disease.

Men with metastatic HSPC were randomly assigned to receive an injection of a testosterone suppression agent (goserelin, leuprolide, or degarelix) with either a 160-mg enzalutamide pill daily or one of three standard Nonsteroidal antti-androgens (bicalutamide, nilutamide, or flutamide).

Overall, there was a 33% decrease in the risk of death in men receiving enzalutamide compared with those who received another nonsteroidal anti-androgen drug.

The increase in survival with enzalutamide was most obvious in men who did not receive docetaxel. Among patients who received enzalutamide without docetaxel, 83% were alive compared with 70% taking another nonsteroidal anti-androgen drug.

Median survival after becoming refractory to hormone therapy is generally less than 1 year.

CRPC with unfavorable CTCs level have decreased overall survival compared with favorable levels, 11.5 vs. 21.7 months (Schaffer DR et al, De Bono JS et al).

Antiandrogen withdrawal response may be observed in up to 30% of patients, and a response to other secondary hormonal manipulations can be seen in up to 65% of patients.

Androgen deprivation as the primary treatment for advanced prostate cancer reduces the PSA by over 95% in 90-99% of patients.

Patients with metastatic hormone sensitive prostate cancer are offered ADT combined with either LHRH agonists or antagonists.

ADT in combination with androgen pathway directive therapy abiraterone plus prednisone, apalutamide, or enzalalutamide, or docetaxel based chemotherapy, are considered in metastatic hormone sensitive prostate cancer.

Tumors from patients with metastatic prostate cancer have a higher degree of vascularization compared to prostate tumors from patients without clinical disease.

There is a higher microvessel density in prostate cancer than in adjacent hyperplastic or benign tissue.

Docetaxel therapy results in a greater than 50% decline of PSA in 38-46% of patients with metastatic prostate cancer refractory to hormones.

TAX 327 trial with 1006 patients with metastatic hormone refractory prostate cancer treated with prednisone 10 mg daily and randomized to docetaxel 75 mg/m2 every 21 days, docetaxel 30 mg/m2 weekly for 5 of every 6 weeks, or mitoxanthone 12 mg/m2 every 21 days for 30 weeks: resulted in median overall survival of 18.9 months in every three week docetaxel group vs 16.5 months in the mitoxanthone group.

TAX 327 trial analysis revealed that administration of every three week docetaxel with prednisone increased survival over the combination of mitoxanthone and prednisone.

Docetaxel survival benefit in hormonally refractive prostate cancer is 20-25% over mitoxanthone and prednisone therapy.

Adding docetaxel to initial androgen deprivation therapy significantly prolongs overall survival among men with metastatic, hormone sensitive prostate cancer (Sweeney C et al).

In the above study the median overall survival was 57.6 months with docetaxel plus ADT compared with 44 months in the ADT arm alone.

The above study suggests upfront chemo-hormonal therapy prolongs overall survival in men with metastatic prostate cancer beginning testosterone suppression.

Upfront docetaxel chemotherapy in addition to hormone therapy suggested significant improvement in survival in early use in newly diagnosed patients with metastatic prostatic disease.

Docetaxel upfront treatment is supported for patients with high volume metastatic prostate cancer.

Mitoxanthone in combination with prednisone increases response rate and longer duration of response without increasing overall survival compared to patients treated with prednisone alone.

Docetaxel increases median survival benefit by 2-3 months compared to mitoxanthone.

Adding docetaxel to ADT improves overall survival in patients with high volume metastatic disease.

Taxane based treatment results in a median time to PSA progression of 6-8 months.

In a randomized study of hormonally refractive patients with metastases treated with docetaxel plus estramustine or mitoxanthone plus prednisone revealed a marked improvement in survival time in the docetaxel and estramustine combination treatment, with a median survival time of 17.5 v. 15.6 months, a median time to progression of 6.3 vs. 3.2 months and PSA declines of at least 50% of 50% vs. 27% with no difference in objective tumor responses.

Docetaxel has proved to prolong survival in advanced castrate resistant prostate cancer (PCa) but in a trial of six courses of docetaxel it does not improve biochemical disease free survival (BDFS) after radical prostatectomy for high risk PCa.

Adjuvant docetaxel without hormonal therapy did not improve PFS after radical prostatectomy for high risk prostate cancer. Instead, docetaxel as monotherapy seems to generate a more rapid biochemical progression in a subgroup of patients.

Docetaxel/estramustine combinations result in a greater than 50% decline in PSA in 68% of chemotherapy naive prostate cancer patients refractory to hormones

Adding thalidomide to docetaxel may produce greater PSA reductions than docetaxel alone in patients with metastatic disease.

Docetaxel added to androgen deprivation therapy does not improve overall survival over androgen deprivation alone in hormone naïve metastatic prostate cancer (GETUG-AFU): this refers to low volume disease.

In the above study there was a significant survival difference in high volume metastatic prostate cancer when docetaxel was added to hormonal therapy.

Adding docetaxel to androgen deprivation therapy significantly improves recurrence free survival compared to a ADT alone in patients with high-risk localized prostate cancer with no apparent long-term toxicity: Whether this benefit translates into improved metastasis free survival is yet unknown (Fizazi K et al).

Epidermal growth factor receptor (EGFR) signaling overexpressed more commonly in African American than in white patients.

Epidermal growth factor receptor (EGFR) signaling crucial for prostate cancer carcinogenesis and is critical to the development of androgen-independent disease.

Presence of HCG� in prostatic cancer cells associated with a poor prognosis.

Longer repeat polymorphisms in IGF1 and CYP19 genes are significantly associated with poorer survival in patients with metastatic disease.

There is a significant increase in risk of prostate cancer specific mortality in patients treated with radiation when core biopsy specimens reveal more than 50% tumor involvement compared to patients with less than 50% involvement on core biopsies.

There is presently no widely accepted method to quantify cancer volume in radical prostatectomy.

Endorectal MRI has a sensitivity of 95% and a specificity of 100% in detecting local recurrence at the site of anastomosis, near retained seminal vesicles and at lateral and anterior surgical margins, suggesting its role in defining local recurrence in patients with rising PSA levels after radical prostatectomy.

Identifying local recurrence after radiation with endorectal MRI is difficult due to prostatic shrinkage and diffuse T2 signal intensity making identification of viable tumor problematic.

A magnetic field strength of al least 1.5 Tesla (T) is required for quality studies of the prostate.

The use of an endorectal coil with a pelvic array coil improves quality of images and is recommended for prostate MRI study.

T2-weighted images provides adequate anatomical imaging of the prostate and is essential for detection, localization and staging of prostate cancer.

Clinical staging for localized prostate cancer T1-T2 has limited utility in predicting outcomes.

In the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) database were analyzed to determine clinical staging by digital rectal examination and transrectal ultrasound found a 35.4% clinical stage error, with more errors in patient downstaging and patient’s lesions were more likely to be staged incorrectly with transrectal ultrasound lesion THAN abnormal digital exam findings (Reese AL et al).

In the above study physicians incorrectly incorporated biopsy results and frequently disregarded transrectal ultrasound findings.

Nearly 25% of patients who develop radiographic progression of metastases do not have a concurrent rise in PSA, a phenomenon known as PSA discordance.

T-2 weighted images cancer of the prostate demonstrates decreased signal intensity within the high signal intense peripheral zone of the prostate.

In prostate cancer T-2 weighted images may have homogenous low signal intensity within the heterogeneous signal intensity transition zone.

MRI spectroscopy may be a reliable test to confirm relapse in prostate cancer after external beam radiation.

Most prostate cancer metastases begin within the marrow and MRI is more sensitive than bone scan or CT scan for identifying such abnormalities.

MR spectroscopic imaging (MRSI) demonstrates cancer based on assessment of concentrations of citrate, creatine, choline and polyamines.

Normal prostate contains high levels of citrate and with prostate cancer the level is reduced or undetectable and the choline level is elevated.

Polyamines are decreased in prostate cancer.

Increased choline+polyamines+creatine to citrate ratio identifies prostate cancer in the peripheral zone on MR spectroscopic imaging (MRSI).

Indium 111 capromab pendetide (ProstaScint) a radiolabeled murine monoclonal immunoglobulin G that recognizes the intracellular epitope of prostate specific membrane antigen utilized to identify with single photon emission tomography (SPECT) lymph nodes in patients with clinically localized disease, and in post prostatectomy patients with rising PSA.

Single photon emission computed tomograpy (SPECT) improves detection of sentinel lymph nodes.

Use of MRI with a lymph node specific contrast agent to identify nodal metastases is a promising technique (Shih).

A trial of selenium and vitamin E (SELECT study) taken alone or together in 35,000 men did not reduce the risk of prostate cancer.

A meta-analysis of 20 epidemiologic studies showed a potential inverse association between toenail, serum, and plasma selenium levels and prostate cancer risk.

NCCN guidleines: Stage I prostate cancer or those at very low risk for recurrence and life expectancy of greater than 20 years, active surveillance is advised.

For men age 65 years at diagnosis followed with active surveillance received an additional six months of quality-adjusted life expectancy compared with treatment with brachytherapy (Hayes JH et al).

The Expanded Prostate Cancer Index Composite quality of life instrument showed that brachytherapy and external being radiation have better preservation of erectile function and urinary continents than does surgery.

The Expanded Prostate Cancer Index Composite quality of life instrument demonstrated lower rates of rectal irritation than did external being radiation, but had higher rates then surgery did.

The Expanded Prostate Cancer Index Composite quality of life instrument Indicated brachytherapy had higher rates of urinary obstructive symptoms than did either external being irradiation or surgery.

In the Prostate Cancer Outcomes study (PCOS) which enrolled 3533 men with prostate cancer diagnosed in 1994 or 1995 and were treated with either surgery or radiotherapy: at 15 years no significant relevant differences in disease specific functional outcomes were observed-men treated for localized prostate cancer commonly have declines in all functional domains during 15 years of follow-up.

In the above PCOS study patients undergoing prostatectomy were more likely to have urinary incontinence than those undergoing radiotherapy at two years and five years, but no difference at 15 years.

In addition in the above study patients undergoing prostatectomy were more likely to have erectile dysfunction at two years and five years, but no significant difference noted at 15 years.

In the above study patients undergoing prostatectomy were less likely to have bowel urgency in two years and five years, and no significant difference at 15 years.

In the SPCG-7 study 875 patients with locally advanced prostate cancer were randomized to total androgen blockade followed by radiotherapy and continuous anti-androgen therapy or hormone treatment alone: At 7.6 years of follow-up there was a 12% reduction in prostate cancer specific mortality in the radiotherapy arm versus the control group, with the combination therapy more than doubling the 10 year survival rate.

Hi intensely focused ultrasound can treat prostate cancer with the goal of reaching a temperature of 100C: it is a minimally invasive technique for the treatment of localized prostate cancer.

High intensely focused ultrasound Involves the delivery of high intensity ultrasound energy from the rectum to coagulate prostate tissue:It is associated with shorter recovery times compared to surgery

Although 16-40% of men with newly diagnosed prostate cancer in the United States meet criteria for active surveillance, less than 10% of men elect this approach.

NCCN guidelines for stge II-IV variable: stage II with a low risk of recurrence, active surveillance for elderly with life expectancy of less than 10 years, but radiation therapy or radical prostatectomy for those with life expeectancy of greater than 10 years.

Prostate Cancer Prevention Trial (PCPT) showed a 25% relative risk reduction in the incidence of prostate cancer with the use of finasteride in the study that included more than 18000 and then was a randomized placebo control study.

Prostate Cancer Prevention Trial (PCPT) the use of finasteride was associated with a 6.4% diagnosis of high grade prostate cancer as opposed to 5.1% in the placebo arm.

Prostate Cancer Prevention Trial (PCPT) Indicated finasteride reduced the risk of prostate cancer by about one third and high-grade prostate cancer was more common in the treatment group than in the placebo group, but after 18 years there was no significant difference in the groups in overall survival, or survival after the diagnosis of prostate cancer (Thompson IM et al).

Oligometastaic cancer defined as the presence of disease in 5 or fewer sites.

Bone scans have proven to only poorly identify metastases, with a 79% sensitivity and 75% specificity.

In the pre – PSA era, regional or distant metastatic disease was noted in approximately 25% of patients at diagnosis, and since the introduction of PSA screening, fewer than 5% of men with prostate cancer are diagnosed with metastatic disease.

Prostate specific membrane antigen (PSMA) expressed in 99% of patients with prostate cancer, and most prominent in patients with castration resistance.

F-Na PET/CT scan is superior to Conventional bone scans in the detection of osseous metastases.

Ga-PSMA-11 scan (prostate specific membrane antigenic) shows promise in the detection of low-volume metastatic disease.

Gallium 68 PSMA-11, is the first drug for PET imaging of prostate-specific membrane antigen positive lesions in patients with prostate cancer.

Sipuleucel in a phase 2 trial of 21 patients with hormonally refractive prostate cancer there was again an overall lack of effect on PSA levels and tumor progression was defined as soft tissue progressive disease, two or more new lesions on bone scan: using this definition the median time to progression was 118 days (Burch PA et al).

In a phase III trial of 127 asymptomatic men with with castrate resistant prostate cancer (CRPC) randomized in a 2:1 ratio, sipleucel-T or placebo: no significant difference in time to tumor progression, but a 4.5 month improvement in overall survival (Small EJ et al).

In a double blind placebo controlled trial involving 512 patients with metastatic castration resistant prostate cancer to receive sipuleucel-T or placebo: there was a reduction of 22% in risk of death with sipuleucel, 4.1 month improvement in survival (Immunotherapy for Prostate Adenocarcinoma Treatment study (IMPACT).

Sipuleucel associated with a discordance between observed survival benefit and lack of effect on disease progression.

Response rate to olaparib in metastatic hormonal resistant prostate cancer 32%.

Responses to olaparib in metastatic hormonal resistant prostate cancer with BRCA2 gene very high.

In men with metastatic castrate resistant prostate cancer who have BRCA 1, BRCA 2, or ATM mutations and who had  disease progression while receiving a new hormonal agent, olaparib lead to significantly longer progression free survival then enzalutamide or abiraterone.

Use of statins in diagnosed patients with nonmetastatic disease shows a 24% reduction in risk for prostate cancer death and a 14% reduction in all-cause mortality (Yu et al).

In patients receiving statins after diagnosis of prostate cancer have a statistically significant reduction in biochemical recurrence after radical prostatectomy.

Treatment with olaparib, a PARP inhibitor in patients with metastatic castration resistant PC with defects in DNA repair had very high response rates.

Variants or other loss of function alterations in homologous recombination DNA (HRD) repair genes are present in about 23% of men with metastatic castrate  resistant prostate cancer.

Loss of HRD genes leads to reliance of tumor cells on single strand DNA repair.

Poly ribose polymerase (PARP) proteins is responsible for single strand DNA repair.

HRD gene mutations plus PARP Iinhibotors leads to cell  death,

In high risk prostate cancer patients the treatment with hormone therapy and the addition of docetaxel chemotherapy improved survival, however the addition of zoledronic acid did not do so (James ND et al).

Among patients with metastatic castration resistant prostate cancer with at least one alteration in BRCA1, BRCA2, or ATM whose disease had progressed on prior treatments treated with olaparib had  a significantly longer duration of overall survival them with patients  is recceiving enzalutamide or abiratone..

Treatment with bone-protecting agents (BPAs) zoledronic acid or denosumab entirely eliminated the risk of fracture as seen in a study of men with metastatic castration-resistant prostate cancer (CRPC) treated with enzalutamide alone or in combination with radium-223.

The use of docetaxel with androgen deprivation therapy in patients with nonmetastatic disease may improve failure free survival but not overall survival.

Apalutamide in patients with metastatic, castration sensitive prostate cancer overall survival and radiographic progression free survival are significantly prolonged will the addition of this drug to androgen deprivation therapy than with placebo plus androgen deprivation therapy.

Compared with abiraterone or enzalutamide, cabazitaxelsignificantly improved clinical outcomes in patients with metastatic castration-resistant prostate cancer who previously received docetaxel plus abiraterone or enzalutamide.

Niraparib approved for treatment of patients with BRCA 1/2-mutant metastatic castration resistant prostate cancer who have previously received taxane based therapy and androgen receptor inhibitor.

Among patients with early-stage prostate cancer the intervention of an increased vegetable consumption diet does not significantly reduce the risk of prostate cancer progression.

Talazoparib shows durable antitumor activity in men with advanced metastatic castrate resistant prostate cancer with DDR-homologous recombination repair gene alterations.