Prostate Cancer- Therapeutics Exam 2

Metastatic Clinical Findings of Prostate Cancer

- Anemia - Back and hip pain - Cord compression . - Pathologic fractures - Lower extremity edema (lots of LN involvement in advanced disease) All these symptoms are signs of bone involvement and metastases.

Abiraterone ADEs

- Arthralgias, myalgias - Diarrhea - UTI - Hypokalemia - *Elevated AST/ALT* - Fluid retention - Hypertension - Adrenocorticoid Insufficiency (Give with prednisone or methylprednisolone). - Interacts with CYP3A4 Inducers and CYP2D6 Substrates

Diet/Lifestyle, Race/Ethnicity, Family History Etiology Prostate Cancer

- Dietary and lifestyle factors are associated with exposure to carcinogens and other factors that promote aberrant cell growth. - Race/Ethnicity is a factor, with the incidence of prostate cancer about 60% more in African Americans than whites. - Family history. Men with a first-degree relative diagnosed with prostate cancer have a 2- to 3-fold increase in risk for prostate cancer.

Clinical Findings of Prostate Cancer

- Dysuria - Increased urinary frequency - Urinary retention - Urinary urgency - Hematuria - Nocturia - Impotence The really early findings of cancer are dysuria, frequency, retention and urgency. Unfortunately, these early findings are also associated with BPH. The later signs (more advanced disease) are Hematuria, Nocturia and Impotence.

Active Surveillance Treatment Modality, Intermediate Risk

- Obtain a PSA no more often than every 6 months - Perform a DRE no more often than every 12 months - Repeat prostate biopsy no more often than every 12 months - Repeat MRI no more often than every 12 months unless there is a clinical indication (in individuals who have PSA increases in the presence of negative biopsies).

Active Surveillance Treatment Modality, Low Risk

- Obtain a PSA no more often than every 6 months - Perform a DRE no more often than every 12 months - Repeat prostate biopsy no more often than every 12 months - Repeat MRI no more often than every 12 months unless there is a clinical indication (in individuals who have PSA increases in the presence of negative biopsies).

Radical Prostatectomy

- Really only reserved for patients whose life expectancy is >10 years, because it is associated with more morbidities than other therapies and it has the potential for more complications (it is a big surgery). - Can cause long-term incontinence, dribbling and ED. - Very bloody surgery as well. - This option is only available when the tumor is confined to the prostate or the prostate bed area.

Adverse Effects of ADT

- Reduced libido and impotence - Hot flashes - Gynecomastia - Osteoporosis - Anemia (Testosterone is important in RBC production) - Decreased mental acuity - Loss of muscle mass, weight gain - Fatigue - Decreased HDL These symptoms are more prevalent in patients who get a bilateral orchiectomy (because it will essentially be permanent), but will be present in patients who get medically castrated.

Brachytherapy

- The insertion of radioactive seeds into the tumor to provide a high amount of local radiation and spare a lot of the normal tissue. Used to boost radiation to the local areas. - Can give done alone or combined with EBRT to boost radiation.

ADEs of LHRH Agonists/Antagonists

- Tumor Flare (Agonists only) - Hot flashes - Loss of libido - Erectile Dysfunction - Shrinkage of penis and testicles - Loss of muscle mass and strength - Fatigue - Depression - Hair loss - Osteoporosis - Obesity - Altered Lipids - Greater risk of DM and CV Disease Regardless of the duration of action, the patient should supplement calcium and Vitamin D while on LHRH therapy.

Imaging Tests in Diagnosis of Prostate Cancer

- Ultrasound, used to guide transrectal biopsies - Bone scan, for patients at high risk of skeletal metastases - Skeletal X-rays, to assess symptomatic areas of pain - CT or MRI can be used to assess fracture risk (this is especially useful in patients who has metastases in large weight-bearing bones).

Other Hormonal Agents for Prostate Cancer

1. Abiraterone 2. Ketoconazole 3. Aminoglutethamide 4. Megestrol 5. Corticosteroids

10+ Years Life Expectancy Treatment, Intermediate Risk Prostate Cancer

1. Active Surveillance 2. Curative Treatment

10+ Years Life Expectancy Treatment, Low Risk Prostate Cancer

1. Active Surveillance 2. Curative Treatment

20+ Year Life Expectancy Treatment Lowest Risk Prostate Cancer

1. Active Surveillance 2. Curative Treatment

>5 Years Life Expectancy OR Symptomatic High or Very High Risk Prostate Cancer Treatment

1. EBRT + ADT 2. EBRT + Brachytherapy + ADT 3. Radical Prostatectomy + Pelvic Lymph Node Dissection - may be followed by EBRT or ADT +/- EBRT if adverse features or LN involvement are present

Radiation for Prostate Cancer

1. External Beam Radiation Therapy 2. Brachytherapy 3. Proton Therapy - Somewhat controversial. It is expensive and requires special equipment that some centers do not have. 4. Radiopharmaceuticals - IV administration of Alpha-emitters. Used in bone disease. Radium-223.

Curative Treatment Treatment Modality, Low Risk

1. External Beam Radiation Therapy (EBRT) or Brachytherapy 2. Radical Prostatectomy +/- Pelvic Lymph Node Dissection (PLND) - PLND may be followed by EBRT or Androgen Deprivation Therapy (ADT) +/- EBRT if adverse features or LN involvement are present. Individuals who get a Pelvic LN Dissection, depending on if they show high-risk features or are positive for LN involvement, can either get EBRT or ADT +/- EBRT following the dissection.

Pharmaceutical ADT Choices

1. LHRH Agonists - Goserelin - Histrelin - Leuprolide - Triptorelin 2. LHRH Antagonists - Degarelix 3. First-Generation Anti-Androgens - Nilutamide - Flutamide - Bicalutamide 4. Second-Generation Anti-Androgens (play a more important role in metastatic prostate cancer) - Apalutamide - Enzalutamide - Darolutamide

Stages of Prostate Cancer

1. Localized- Stage I, Stage IIA/B/C, Stage IIIA 2. Locally Advanced- Stage IIIB/C 3. Metastatic- Stage IVA/B If the tumor has LN involvement, it is automatically a Stage IVA. If there are metastases, it is automatically a Stage IVB. Treatment of prostate cancer is based on the Stage Category, which is the Localized, Locally Advanced, or Metastatic.

5 or Less Years Life Expectancy AND Asymptomatic High or Very High Risk Prostate Cancer Treatment

1. Observation 2. ADT 3. EBRT

Surgical Procedures for Prostate Cancer

1. Radical Prostatectomy 2. Transurethral Resection of the Prostate (TURP) 3. Cryosurgery 4. Pelvic Lymph Node Dissection (PLND)

First-Generation Anti-Androgen ADEs

ALL First-Generation: - Metallic Taste - Diarrhea (Dose-Limiting with Flutamide) - Abdominal Cramps - Gynecomastia Nilutamide-Specific - Light-dark adaptation disorders - Alcohol intolerance - Interstitial Pneumonitis - Hepatic Dysfunction (monitor for ALL first-generation, but mostly seen with nilutamide)

Second-Generation Anti-Androgens ADEs

ALL Second-Generation: - Fatigue - Rash - Diarrhea - Nausea - Arthralgias - Peripheral edema - Falls - Fractures - Significant DDIs! Enzalutamide-Specific: - Seizures (decreased seizure threshold) - Hypersensitivity reactions - Posterior Reversible Encephalopathy Syndrome (swelling in the posterior portion of the brain, causing headache, confusion, seizures, and visual loss)

Abiraterone

Abiraterone is a hormone synthesis inhibitor, and is typically given with either prednisone 5mg daily or methylprednisolone 4mg twice a day, depending on the clinical trial that is cited. Its bioavailability is much, much higher when taken with food, so it is suggested to take Abiraterone at 250mg/day with a low-fat breakfast as an alternative to 1000mg/day in the morning after an overnight fast (this is controversial, but is in the NCCN guidelines). It saves the patient money this way.

10-20 Year Life Expectancy Treatment Lowest Risk Prostate Cancer

Active Surveillance is the main treatment strategy: - Obtain a PSA no more often than every 6 months - Perform a DRE no more often than every 12 months - Repeat prostate biopsy no more often than every 12 months - Repeat MRI no more often than every 12 months unless there is a clinical indication (in individuals who have PSA increases in the presence of negative biopsies).

Bone Metastases and Treatment in Prostate Cancer

Bone metastases can occur in >90% of patients with CRPC, and these patients are at risk for cord compression, pathologic fractures, and bone pain. Bone Metastases can be treated with: - Zoledronic Acid 4mg IV every 3 to 4 weeks (studies do show every 12 weeks is just as beneficial) - Denosumab 120mg SQ every 4 weeks. Patients who started on denosumab had a longer time to 1st skeletal event compared to zoledronic acid (20.7 months vs 17.1 months). There were similar rates of radiation therapy, pathologic fracture and cord compression. Denosumab patients had a greater incidence of hypocalcemia.

Common Sites of Metastasis for Prostate Cancer

Bones Liver Lungs Brain (not frequently)

Inflammation and Prostate Cancer

Chronic Inflammation. Chronic inflammatory states, like chronic pancreatitis or other conditions results in an inflammatory proliferative atrophy of prostate cancer cells. This results in a pre-malignant lesion referred to as Prostatic Intraepithelial Neoplasia (PIN). This is a precursor to prostate cancer.

ADT Role in Prostate Cancer

Early on in Prostate Cancer, the growth is supported by androgens, primarily testosterone produced by the testes (95%), but also from the Adrenal Glands. Thus, blockade of androgen production can starve the tumor and hinder its growth. This is a very important strategy to stop the growth of cancer. Continuous administration of GnRH Agonists or Antagonists leads to high levels of GnRH in the blood, which acts as a negative feedback on the hypothalamus, causing the body to stop producing GnRH, inhibiting production of LH by the pituitary and therefore inhibiting production of testosterone from the testes. Another strategy is to inhibit the uptake of androgens by the tumor by using anti-androgen medications.

Curative Treatment Treatment Modality, Intermediate Risk

External Beam Radiation Therapy (EBRT) or Brachytherapy Radical Prostatectomy +/- Pelvic Lymph Node Dissection - This may be followed by EBRT or ADT +/- EBRT if adverse features or LN involvement are present Individuals who get a Pelvic LN Dissection, depending on if they show high-risk features or are positive for LN involvement, can either get EBRT or ADT +/- EBRT following the dissection.

Anti-Androgen Therapy

First-Generation - Flutamide - *Bicalutamide* (most commonly used, it is once daily and has a better ADE profile compared to the other two) - Nilutamide Second-Generation (works via a different mechanism, these are more potent blockers, but have more ADEs. They have a much more significant interaction with the AR) - *Enzalutamide* - Apalutamide - Darolutamide

<10 Year Life Expectancy Treatment Lowest Risk Prostate Cancer

For individuals with less than a 10 year life expectancy the main treatment option is Observation (AKA Active Surveillance). When or if they start developing symptoms from prostate cancer, palliative treatment is started.

<10 Years Life Expectancy Treatment, Intermediate Risk Prostate Cancer

For individuals with less than a 10 year life expectancy the main treatment option is Observation or EBRT or Brachytherapy. 1. Observation - When or if they start developing symptoms from prostate cancer, palliative treatment is started. 2. EBRT 3. Brachytherapy

<10 Year Life Expectancy Treatment, Low Risk Prostate Cancer

For individuals with less than a 10 year life expectancy the main treatment option is Observation. When or if they start developing symptoms from prostate cancer, palliative treatment is started.

Treatment Approach for Prostate Cancer

General approach to treatment is based on: 1. The extent of the disease (Disease Stage): Is the cancer confined to the prostate gland? 2. Symptoms: Presence of symptoms. 3. Gleason Score: Biology of the tumor. 4. Life Expectancy: Is the patient expected to live long enough to benefit from the treatment?

Germline Mutations and Prostate Cancer

Germline mutations in DNA repair genes. There are a number of these associated with increased risk of prostate cancer. Numerous other genetic susceptibilities may be linked although there is not strong evidence and is unclear. There are certain germline mutations (RNASEL, ELAC2 and MSR1) that result in Proliferative Inflammatory Atrophy, which may lead to additional chromosomal abnormalities (especially chromosome 8) that result in PIN. Further genetic changes, like loss of the PTEN tumor supressor gene, and mutations in the amplification of the Androgen Receptors can all result in the development of prostate cancer.

Gleason Grade Group

Grade 1: Score of 6 or less. Grade 2: Score of 7 Grade 3: Score of 7 Grade 4: Score of 8 Grade 5: Score of 9 or 10

Characteristics of Prostate Cancer

Greater than 95% of prostate cancers arise in the gladular epithelium of the peripheral glands of the prostate. This is in contrast with BPH, which typically arises from the central and periurethral portions of the prostate. Prostate cancer tends to spread via the lymph nodes and the blood and tends to spread to both regional and distal lymph nodes, the bone, liver, lungs and sometimes (but not frequently) the brain.

Screening for Prostate Cancer

Has changed dramatically over the past few decades. This is because screening for prostate cancer has led to an overdiagnosis, particularly at stages where treatment will have very little to no benefit on overall survival. Routine screening for prostate cancer is no longer recommended. There are three organizations that have different routes to take for Prostate Cancer screening. - USPSTF - ACS - NCCN

Treatment Approach for High or Very High Risk Prostate Cancer

High Risk is characterized as T3a, OR PSA >20, OR Grade Group 4 or 5 (Score of 8 or 9). Very High Risk is characterized as T3b/c These patients are categorized based on life expectancy as well, but the categories are a lot more stringent (<5 and 5+ years) and they depend on the presence of symptoms. Regardless of the life expectancy, these patients are going to be candidates for curative therapies and treated more aggressively. 1. >5 year life expectancy OR symptomatic 2. 5 or less years life expectancy AND asymptomatic

Castration-Naive Metastatic Prostate Cancer Treatment

Individuals who have not received initial therapy and are castration-naive will be candidates for: 1. Total Androgen Blockade (TAB, LHRH Agonist with an Anti-Androgen). 2. Testosterone Reduction with an LHRH agonist/antagonist or an orchiectomy. 3. ADT + Abiraterone + Corticosteroid (Prednisone or Methylprednisolone). If individuals start on TAB, but discontinue the anti-androgen later on, they could go into something called Anti-Androgen Withdrawal.

Development of Castrate-Resistant Prostate Cancer

Initially, prostate cancer growth is androgen-dependent. Thus it requires the interaction of the active form of testosterone, dihydrotestosterone, on the androgen receptor. It then becomes phosphorylated and results in signals that promote cell proliferation and tumor growth. Eventually prostate cancer can become androgen-independent, AKA Castrate-Resistant Prostate Cancer. It is believed this is due to mutations in the Androgen Receptor that can occur, such that the AR can bind to other ligands (other than DHT), become ligand-independent and/or become amplified to promote the growth of the tumor. Thus the strategies to inhibit tumor growth now change to not only rely on continuous inhibition of androgen production, but to target adrenal androgen production and the AR directly.

Cryosurgery

Insertion of a probe that is supercooled to freeze the tumor and rethaw it over and over until the tumor is destroyed.

Treatment Approach for Prostate Cancer, Intermediate Risk

Intermediate Risk is characterized as T2b/c, OR a Grade Group 2-3 (Gleason Score of 7), OR a PSA of 10-20. Treatment for the Intermediate Risk patients is broken down into life expectancy, like before. 1. 10+ Years Life Expectancy 2. <10 Years Life Expectancy However, there is a subgroup of these patients who have very unfavorable characteristics, even though they are still considered Intermediate Risk. This category is Intermediate Risk with Unfavorable Features. The treatment strategy here is usually more aggressive and definitive. This category is also broken down into life expectancy. 1. 10+ Years Life Expectancy 2. <10 Years Life Expectancy

Ketoconazole MOA for Prostate Cancer

Ketoconazole is an antifungal that also inhibits CYP17A1, like Abiraterone, but specifically inhibits the 17,20-alpha hydroxylase activity of the enzyme. Inhibition of this reaction blocks the conversion of 17 alpha-hydroxyprogesterone into Androstenedione, and 17a-hydroxypregnenolone into Dihydroepiandosterone. Androstenedione is the direct precursor to testosterone, whereas DHEA is the direct precursor to Androstenedione.

LHRH Therapy

LHRH Therapy (for both Operable and Metastatic Prostate Cancer) are all injectables (either SQ or IM) and can be monthly injections, every 3 months, or every 6 months. There were longer formulations at one time (once yearly injections), but those were taken off the market because of the ADEs that are associated with LHRH therapy and that some patients benefit more with intermittent LHRH Therapy. Patients who do not achieve adequate testosterone suppression (<50 ng/mL), termed *Castrate-Level*, should be considered for additional hormonal manipulation.

Abiraterone MOA and Monitoring

MOA: Blocks CYP17A1, which is responsible for two hydroxylation reactions important in androgen and glucocorticoid synthesis, 17-alpha-hydroxylase and 17,20-alpha hydroxylase. Abiraterone specifically inhibits the 17-alpha-hydroxylase reaction, which converts Pregnenolone and Progesterone into 17a-hydroxypregnenolone and 17a-hydroxyprogresterone. These two compounds are precursors to the first androgens created in steroidogenesis. Abiraterone also inhibits the 17,20a- hydroxylase, albeit at a lower selectivity. Overall this reduces androgen production, but at a cost, as it inhibits cortisol synthesis as well. Patients on Abiraterone need to have their LFTs monitored, especially AST, ALT and Bilirubin every 2 weeks for the first 3 months of therapy then can decrease to monthly monitoring. Patients will also need their potassium and BP monitored monthly while taking Abiraterone.

Digital Rectal Exam Features

Normal prostate gland texture is smooth and elastic in texture, about the consistency as the tip of the nose. In BPH, the prostate is smooth, but the texture is more rubbery. In cancer, the prostate may be felt as a rock-hard nodule or a mass. A biopsy would then be necessary for the diagnosis.

Subsequent Therapy in Metastatic Prostate Cancer

Once the prostate cancer becomes castrate-resistant (so it starts to grow again after initial therapy with hormonal therapy), there are a number of agents that may be used. 1. Hormonal Agents 2. Cytotoxics 3. Pembrolizumab (if MSI-H/dMMR) 4. Immunotherapy (Sipuleucel-T) 5. Radium-223

Active Surveillance Treatment Modality, Lowest Risk

One of the treatment options for 20+ Years Life Expectancy in those with Very Low Risk Prostate Cancer. This may be a treatment modality in other risk categories of Prostate Cancer. - Obtain a PSA no more often than every 6 months - Perform a DRE no more often than every 12 months - Repeat prostate biopsy no more often than every 12 months - Repeat MRI no more often than every 12 months unless there is a clinical indication (in individuals who have PSA increases in the presence of negative biopsies).

Curative Treatment Treatment Modality, Lowest Risk

One of the treatment options for 20+ Years Life Expectancy in those with Very Low Risk Prostate Cancer. This may be a treatment modality in other risk categories of Prostate Cancer. 1. External Beam Radiation Therapy (EBRT) or Brachytherapy 2. Radical Prostatectomy +/- Pelvic Lymph Node Dissection - This may be followed by EBRT or Androgen Deprivation Therapy (ADT) +/- EBRT if adverse features or LN involvement are present. Individuals who get a Pelvic LN Dissection, depending on if they show high-risk features or are positive for LN involvement, can either get EBRT or ADT +/- EBRT following the dissection.

Treatment Overview of Operable Prostate Cancer

Patients diagnosed with prostate cancer that is considered operable (confined to the prostate gland with limited extension) are candidates for a variety of treatments, based on their life expectancy and their risk of dying from cancer (if the cancer will be a problem later on in life). These risk categories are: - Very Low Risk - Low Risk - Intermediate Risk - High Risk - Very High Risk. Patients with asymptomatic early-stage disease usually have excellent 10-year survival. Treatment morbidities must be balanced with lower risk of dying from cancer.

Visceral Disease Metastatic Prostate Cancer Treatment

Patients who do have visceral metastases with their metastatic prostate cancer are candidates for: 1. Abiraterone + Prednisone/Methylprednisolone 2. Docetaxel 3. Enzalutamide (2nd-generation Anti-Androgen) 4. Mitoxantrone with Prednisone 5. Clinical Trial These patients are candidates for all the non-visceral disease treatments EXCEPT for Radium-223.

Radiation Consequences

Patients who get EBRT can experience complications that include bowel disruptions (passing mucus, loss of control), diarrhea, hematuria, urinary retention, impotence, incontinence, genito-urinary strictures. Can persist for months after the radiation is given. Radiation, especially to the pelvic area, can cause substantial myelosuppression because that is where most, if not all, of the blood cells are grown in the bone marrow. This can be compounded if the person is receiving other medications/treatments that can cause myelosuppression.

Treatment of Metastatic Prostate Cancer

Patients with metastatic prostate cancer, specifically castration-naive disease, will be treated with ADT (normally now with chemotherapy [docetaxel], a first-line recommendation). This is the gold-standard treatment for castration-naive metastatic prostate cancer. In this setting, intermittent ADT may be associated with better QoL than continuous ADT (less ED, greater mental health). Metastatic Cancer initial treatment (for adenocarcinoma, specifically) is based on the presence of visceral metastasis.

Non-Visceral Disease Metastatic Prostate Cancer Treatment

Patients without visceral metastases but have metastatic prostate cancer are candidates for: 1. Abiraterone + Prednisone/Methylprednisolone 2. Docetaxel 3. Enzalutamide (2nd-generation Anti-Androgen) 4. Radium-223 5. Clinical Trial

PLND

Pelvic Lymph Node Dissection (PLND) - This is the removal of node-bearing tissue - This procedure is associated with an increased likelihood of finding lymph node metastases which will provide a more complete staging of the prostate cancer, which may increase the aggressiveness of therapy.

Hormonal Agent Options for CRPC

Primary Therapies - Abiraterone + Corticosteroid (Prednisone/MP) - 2nd-Generation Anti-Androgen Secondary Therapies - Ketoconazole - Aminoglutethimide - Megestrol - Corticosteroids

Prostate Cancer, Epidemiology

Prostate cancer is the top cause of cancer in men and the second top cause of cancer-related deaths in men overall. It accounts for about 19% of new cancer cases in men. Incidence is about 60% higher in African Americans than whites, and mortality is twice as high in African Americans vs. whites. Overall the risk of prostate cancer in men is a 1 in 11-12 lifetime risk. 90% of cases discovered at the localized or regional stage have a 5-year survival of almost 100% whereas the 5-year survival is only 31% if the prostate cancer is metastatic.

Diagnosis and Evaluation of Prostate Cancer

Prostate cancer type and severity is characterized by: - the DRE - the radiographical clinical T stage (tumor size) - the Gleason Score - extent of cancer in prostate biopsy - serum PSA level. These factors all are used in risk stratification (proposed by the NCCN), which helps to determine treatment.

PSA

Prostate-Specific Antigen This is one of the tumor markers for prostate cancer, and is usually elevated in patients with prostate cancer. The downside to PSA is that many medications do falsely elevate the number, which increases the chance for a false diagnosis. PSA values should be adjusted appropriately for concomitant medications that are known to elevate the PSA (finasteride, dutasteride). Prostate examinations (like DRE) can also falsely elevate PSA in the short term.

Proton Therapy and Radiopharmaceuticals

Proton Therapy - Somewhat controversial. It is expensive and requires special equipment that some centers do not have. Radiopharmaceuticals - IV administration of Alpha-emitters, typically Radium-223. This is only used in bone disease.

Lab Tests in Diagnosis of Prostate Cancer

Required Lab tests include: - CBC - LFTs (sometimes prostate cancer spreads to the liver) - Acid/Alkaline Phosphatase (can be secreted by both liver and the bone).

ADT Use in Clinically Localized Prostate Cancer

Short-Term ADT (about 4-6 months) when added to radiation when attempting definitive treatment for clinically localized (N0, M0) prostate cancer can improve overall and cancer-specific survival in men with intermediate and high-risk disease. It does add ADEs, of course. Four months of ADT is likely sufficient, and it is given before and during EBRT. Other treatment options for ADT in Localized and Locally Advanced Disease are: - Orchiectomy - LHRH Agonist alone - LHRH Agonist PLUS 1st-Generation Anti-Androgen (results in TOTAL androgen blockade)

Gleason Score

Staging of prostate cancer involves determining the extent of the disease spread, but also involves the Gleason Score, which is determined by primary and secondary histopathiological growth features of the tumor. The gleason score essentially tells us the biology of the disease and how indolent it is. The scale is broken down into two scores that are added together to get a total Gleason Score. Both scores are based on the Gleason's Pattern Scale, which is a scale of 1-5 that describes the pattern of the cells in the tumor and how differentiated the cells are. There is a correlation between the Gleason Score and survival! The Gleason Score can be converted to a Grade, and the higher the grade, the higher the Stage of the cancer.

Cytotoxic Agent Options for CRPC

Taxanes - Docetaxel - Cabazitaxel Mitoxantrone + Prednisone - Not commonly used anymore as Mitoxantrone is an anthracenedione, part of the anthracycline class of drugs, so there are more toxicities with this regimen than with Taxanes.

American Cancer Society Prostate Cancer Screening

The American Cancer Society encourages men aged 50 at average risk with a life expectancy of 10 or more years to discuss screening with their PCP. Individuals at high risk (African Americans, or those with a close relative diagnosed before the age of 65) should begin the discussion at the age of 45. If the patient has several close relatives diagnosed at an early age, the screening discussion should begin at age 40.

NCCN Prostate Cancer Screening

The National Comprehensive Cancer Network (NCCN) no longer recommends screening guidelines for men at average risk, but they do agree that it is reasonable to begin informed testing at the age of 45. This informed testing includes a baseline PSA, DRE at age 45 and get repeated testing based on their risk assessment.

USPSTF Prostate Cancer Screening

The USPSTF recommended against PSA screening in 2012. In the updated guidelines, the USPSTF recommended against screening any man 70 years of age or older and in patients 55-69, screening should only be done after an individualized, informed decision-making discussion.

Clinical Features of Prostate Cancer

The clinical features vary based on the glandular involvement and obstruction to nearby structures. There are common: - Clinical Findings - Features during Advanced Disease (Metastatic Features) - Features on a Digital Rectal Exam - PSA Features. Even with all these clinical features, many patients who have prostate cancer are asymptomatic.

Gleason's Pattern Scale

The scale that is used to determine the two scores (primary and secondary growth patterns) that comprise the total Gleason Score. 1- Small, uniform cells in the gland. Well-differentiated. 2- Cells have more space (stroma) between the glands. Still relatively differentiated. 3- Distinctly infiltration of cells from glands at the margins. Moderately differentiated to Poorly differentiated and Anaplastic. 4- Irregular masses of neoplastic cells with few glands. Poorly Differentiated and Anaplastic. 5- Lack of or occasional glands, sheets of cells. Poorly Differentiated and Anaplastic.

Androgen Deprivation Therapy

Used as a primary systemic therapy for both regional and advanced prostate cancer. There are also strategies to used ADT before surgery (neoadjuvant), through the surgery and after surgery (adjuvant) all combined with radiation therapy for both localized or locally advanced disease (nonmetastatic). ADT for castration-naive Prostate Cancer can be done via: - Bilateral Orchiectomy (removal of testes, drops testosterone FAST. Has an advantage in vertebral involvement where we avoid a tumor flare, and do not get a cord compression) - LHRH Agonist or Antagonist (Antagonist will not cause a tumor flare, Agonist will) - LHRH Agonist plus First-generation Anti-Androgen (which can be continued for the first two weeks or continued indefinitely with the LHRH Agonist, this technique is to avoid the tumor flare) The goal of ADT is to maintain castrate levels of testosterone in the serum (<50 g/dL)

Clinical T Stage of Prostate Cancer

Used in the early evaluation of prostate cancer. Sometimes can be determined via an exam, but can also get this from an imaging scan (CT, MRI). T1 - Unapparent tumor that is not palpable T2 - Palpable tumor but confined within the prostate T3 - Extraprostatic tumor that is not fixed and does not invade into adjacent structures T4 - Very large tumor that is fixed or invades adjacent structures other than seminal vesicles

Treatment Approach Operable Prostate Cancer, Lowest Risk

Very Low Risk patients have Prostate Cancer that is characterized as T1c AND PSA <10 AND Grade Group 1. Treatment is determined based on the life expectancy of the patient: - 20+ Life Expectancy - 10-20 Life Expectancy - <10 Life Expectancy

TURP

Transurethral Resection of the Prostate (TURP) - This can be done to relieve urinary symptoms for those unable or unwilling to undergo a Radical Prostatectomy.

Complications of Radical Prostatectomy

1. Urinary Incontinence 2. Erectile Dysfunction 3. Anastomotic Strictures These can persist for the rest of the patient's life.

Operable Disease Treatment Risk Categories

1. Very Low Risk - T1c + PSA <10ng/mL + Grade group #1 2. Low Risk - T1-T2a + PSA <10ng/mL + Grade group #1 3. Intermediate Risk - T2b/c OR Grade Group 2 or 3 (Score of 7) OR PSA 10-20 ng/mL 4. High Risk - Stage T3, a Gleason Score of 8-9, or a PSA >20 ng/mL 5. Very High Risk - T3b and T4 Disease - Usually these patients are not candidates for a radical prostatectomy because of the extensive local spread of the disease. Radical Prostatectomies are considered to be a curable option, but since we cannot be sure we have removed all of the tumor, then the surgery is not worth it. Lots of morbidity with a RP.

Gleason Score Ranges

A Gleason Score of 2-4 reflects indolent, well-differentiated tumors. A score of 5-7 reflects a moderately differentiated and aggressive tumor and a score of 8-10 reflects a nasty tumor that has the greatest possibility of advanced spread.

ADEs of Ketoconazole for Prostate Cancer

ADEs include: - Hepatocellular necrosis - Impaired cortisol response - GI Intolerance - Mouth sores Ketoconazole needs to be administered with physiologic hydrocortisone. This medication is poorly tolerated due to GI intolerance, and is hepatotoxic.

Anti-Androgen Withdrawal

A phenomenon that occurs in about 30% of patients that are on LHRH Agonists + 1st-Generation Anti-Androgen. If the anti-androgen is dropped and only remain on the LHRH Agonist, the tumor can shrink! The androgen receptor is very able to mutate, and it may be possible that the presence of both the LHRH Agonist and the Anti-Androgen are driving the growth of the tumor, due to a mutation. If we take the anti-androgen away, we change the environment and the tumor will shrink. If we have a patient on continuous Anti-Androgen therapy with an LHRH Agonist and they have tumor progression, it is reasonable to just drop the ant-androgen and monitor for their response! The time to response is usually >6 weeks, but the duration of the response can last from 3.3 to 14.5 months, with the median response about 4 months.

Treatment of ADEs of LHRH Agonists/Antagonists

Hot Flashes: - *Venlafaxine* (primary therapy) - Gabapentin - SSRIs, SNRIs Osteoporosis (treatment for life): - Screen and treat for osteoporosis and if at risk treat with: - Denosumab 60mg SQ every 6 months - Zoledronic Acid 5mg IV annually (do not use in severe renal function!) - Alendronate 70mg weekly - Supplement Vitamin D and Calcium

Favorable vs. Unfavorable Intermediate Risk Stratification for Prostate Cancer

If someone has 1 of those Intermediate risk factors AND is a Grade Group 1, they are Favorable. If someone has 2+ of those risk factors above OR they are Grade Group 3, they are Unfavorable.

Treatment of Recurrent Prostate Cancer (Non-metastatic)

If the prostate cancer comes back, and is still only in the localized site then the patient may still be a candidate for a Radical Prostatectomy. The patient could also move onto the 2nd generation anti-androgen, or a secondary hormonal therapy (like ketoconazole). Therapies like Abiraterone and cytotoxics are generally reserved for metastatic prostate cancer, so they would not be used in these situations.

SBRT

Image-Guided Stereotactic Body Radiation Therapy. This technique is more precise and delivers more radiation in less fractions. SBRT delivers highly conformational, high-dose radiation in 5 or fewer treatment fractions.

Tumor Flare

In patients who get TAB, an anti-androgen is given with the LHRH Agonist for at least 7 days to prevent a tumor flare, which can cause emergent complications if there are bone metastases, especially in the spine. Upon initiation of the LHRH Agonist, the body will produce a LOT of testosterone at first because of the initial rise of LH stimulation, and after about 7 days the body experiences the negative feedback and stops testosterone production. An anti-androgen will prevent the tumor from "flaring" and have a growth spurt and become more symptomatic initially because of the androgen receptor blockade. After the tumor flare period is over, these patients may D/C the anti-androgen.

ADT Use for Regional Disease

In patients who have regional involvement (N1, M0) disease and have a life expectancy of >5 years can be treated with EBRT and neoadjuvant, concurrent and/or adjuvant ADT (as with N0, M0 disease) OR ADT alone OR ADT plus Abiraterone. ADT Alone or w/ Abiraterone Treatment Options - Orchiectomy +/- Abiraterone - LHRH Agonist/Antagonist +/- Abiraterone - LHRH Agonist + 1st-Generation Anti-Androgen Individuals who undergo a radical prostatectomy who have positive LN involvement should be started on ADT immediately after surgery, as it improves overall survival compared to those who wait to start ADT after surgery.

ADT Use in Recurrence/Persistence PSA After Curative Therapy

In some patients, PSA can remain elevated, go down but elevate again or starts to increase from baseline after definitive therapy with a Radical Prostatectomy or EBRT (in non-metastatic disease). These patients may have persistent prostate cancer or recurrence of their prostate cancer somewhere else. It is unclear whether immediate starting of ADT or waiting to start is the most beneficial, especially in patients who are asymptomatic. The decision is going to depend on the patient's prognosis, the rate of PSA increase (if it is a steep slope over a gradual rise) and other disease state factors. Some individuals may not want to start ADT right away, due to ADEs. If the cancer is more aggressive (steep increase in PSA) or more advanced disease will probably benefit from earlier treatment of ADT rather than later. If the patient did not get EBRT, then the patient may be a candidate for ADT as well. In this setting, Intermittent ADT was shown to not be inferior (but also not superior) to continuous ADT.

Aminoglutethimide for Prostate Cancer

MOA: Inhibits a wide variety of enzymes in the steroidogenesis pathway, most notably the conversion of cholesterol to pregnenolone, which is the precursor to all androgens, glucocorticoids and mineralocorticoids. Aminoglutethimide basically inhibits all androgen, cortisol and aldosterone production. This medication is rarely used anymore due to the profound effect it has on steroidogenesis. ADEs include: - Adrenal suppression - Drowsiness - Rash - Nausea - Anorexia Needs to be administered with a corticosteroid.

Megestrol for Prostate Cancer

MOA: Inhibits the release of LH from the pituitary (via negative feedback) and can act as an anti-androgen at the target tissue level. ADEs include: - Fluid retention - Nausea/Vomiting - Weight gain (usually from the fluid retention) - Breast tenderness - Venous Thrombosis - Increased appetite

Corticosteroids for Prostate Cancer

MOA: Suppresses ACTH production, which leads to a suppression of adrenal production of androgens. May also help with pain. These are usually given in conjunction with Abiraterone, Ketoconazole, or Aminoglutethimide to prevent the adrenal suppression that can manifest with those medications, but can also be used in late prostate cancer to suppress ACTH and block androgen production at the adrenal glands. Prednisone, Methylprednisolone or Dexamethasone are typically used.

EBRT

Most commonly used radiation therapy for Prostate Cancer, and can be performed as: - Intensity-Modulated Radiation Therapy - Hypofractionated Radiation (they go twice a day) - Image-Guided Stereotactic Body Radiation Therapy. Complications include bowel disruptions, diarrhea, hematuria, urinary retention, impotence, incontinence, genito-urinary strictures. Can persist for months after the radiation is given.

Prostate Cancer Etiology/Risk Factors

There are a number of factors that contribute to etiology. 1. Dietary and Lifestyle Factors 2. Race/Ethnicity 3. Family History 4. Germline Mutations 5. Chronic Inflammation

10+ Years Life Expectancy Treatment, Unfavorable Intermediate Risk Prostate Cancer

These patients will probably get more definitive treatment, and will not be candidates for Active Surveillance like the other groups. 1. Radical Prostatectomy +/- Pelvic Lymph Node Dissection - may be followed by EBRT or ADT +/- EBRT if adverse features or LN involvement are present. 2. EBRT +/- ADT 3. EBRT + Brachytherapy +/- ADT

PSA Findings

This is a prostate-specific marker, but not cancer-specific marker. There are non-malignant causes of elevated PSA in males (medications like finasteride and dutasteride). Normal PSA is about 0-2.5 ng/mL. Elevated PSA of 4-10 indicates cancer in about 1/3 of all patients (30-35% chance of cancer), whereas a PSA >10 is associated with a 67% chance of prostate cancer. PSA of 10 or higher is definitely an indication to test for prostate cancer.

Radium-223

This is an Alpha-Emitting radiopharmaceutical that is directed toward bone metastases in prostate cancer. It has historically been used for decades in prostate cancer. It has been shown to extend survival in patients with castrate-resistant prostate cancer who have symptomatic bone metastases, but do not have visceral bone metastases. Alpha-Emitting radiopharmaceuticals differ from the Beta-Emitting radiopharmaceuticals (like Samarium 153 and Strontium 89). These two radiopharmaceuticals are palliative (they reduce pain and complications from bone metastases) but provide no survival advantage. Radium-223, when administered IV, binds preferentially to hydroxyapatite in osteoblastic bone metastases. It concentrates in and around the bone disease and delivers radiation. Radium-223 is administered once a month IV for 6 months. The main toxicity is myelosuppression, with mild GI effects (nausea, diarrhea, vomiting). Because of the myelosuppression, we need to check the patient's CBC prior to each dose, especially the platelet count, Absolute Neutrophil Count and hemoglobin, and make sure these all meet the criteria level before administration. Also because of the myelosuppression, Radium-223 is not administered with chemotherapy (outside of clinical trials), as it will both exacerbate the myelosuppression and limit the dose we can give of the chemotherapy. It has also been noticed that patients who had prior R-223 have issues tolerating or responding to systemic chemotherapy after R-223 has been fully administered.

Cord Compression and Treatment

This is emergent complication due to bone metastasis of various cancers that can cause paralysis of every nerve below the compression. The bone metastasis on the spine grows and starts to compress the spinal cord, which inhibits the functioning of the nerves at and below the site of compression. Patients will lose control of functions below the compression, and if left untreated immediately (>24 hours) paralysis is common. If someone who has cancer presents with back pain, especially a sudden worsening, and we know they have bone metastases, they should be started immediately on corticosteroids, get a scan (MRI) and if they do have a cord compression then surgery or radiation is used to treat.

Treatment Approach for Prostate Cancer, Low Risk

To be characterized as Low Risk Prostate Cancer, the cancer has to be T1-T2a AND PSA <10 AND Grade Group 1. Treatment for the Low Risk patients is broken down into life expectancy, like before. 10+ Years Life Expectancy <10 Years Life Expectancy

Decreased Bone Mineral Density in Prostate Cancer

Treatment with LHRH Agonists/Antagonists can cause osteopenia, a loss of bone density, and asymptomatic vertebral fractures. Long-term treatment with ADT can lead to significant osteoporosis. Patients with major risk factors for decreased BMD include - Chronic alcohol and/or tobacco use - Sedentary lifestyle - Strong family history of osteoporosis - Chronic use of drugs that can reduce bone mass (like corticosteroids)

<10 Year Life Expectancy Treatment, Unfavorable Intermediate Risk Prostate Cancer

Unlike other categories with life expectancy less than 10 years, these patients are still candidates for more aggressive therapy. 1. EBRT +/- ADT 2. EBRT + Brachytherapy +/- ADT 3. Observation