Prostate Cancer

2nd Hormonal Therapy

If initial ADT has failed, a variety of strategies (including antiandrogen withdrawal, and administration of antiandrogens, abiraterone, high dose of ketoconazole, or estrogens may afford clinical benefit, however, none of these has yet been demonstrated to prolong overall survival in the pre-chemotherapy setting.

Cancer Characteristics

If malignant, growth can be very slow with a doubling time of 2 or more years If advanced, skeletal metastatic involvement is the most common Most of patients may have hypercalcemia Metastatic disease can also spread to the liver, lungs, brain and adrenal glands

Cabazitaxel (Jevtana)

In combination with prednisone for the treatment of patients with hormone-refractory metastatic prostate cancer previously treated with a docetaxel-containing treatment regimen

Ketoconazole (Nizoral) DDIs

Requires acid environment for dissolution and absorption (PPI's, H2-blockers, antacids, sucralfate) Inhibits CYP3A4 & has major drug interactions

Cabazitaxel (Jevtana) MOA

Same as other taxanes Unlike other taxanes, cabazitaxel has a poor affinity for multidrug resistance (MDR) proteins, therefore conferring activity in resistant tumors.

Cabazitaxel (Jevtana) DDI

Substrate of CYP3A4 (like paclitaxel and docetaxel)

Hormone Therapy

1.GnRH analogs (LH-RH analogs) 2.Anti-androgens 3.Antiandrogen withdrawal 4.GnRH (LHRH) antagonist 5.17 α-hydroxylase/C17,20-lyase (CYP17) inhibitor:abiraterone 6.Ketoconazole +/- glucocorticoids 7.5-alpha-reductase inhibitors 8.Estrogens/Progestins 9.Bilateral orchiectomy

Sipuleucel-T (Provenge) Steps

1.Peripheral blood is collected from the patient via leukapheresis, from which peripheral blood mononuclear cells (PBMCs) are isolated. 2.Antigen presenting cell (APC) precursors, consisting of CD54-positive cells that include dendritic cells are isolated from the PBMCs. 3.The APCs are then activated (in vitro) with a recombinant human fusion protein, PAP-GM-CSF, composed of an antigen specific for prostate cancer, prostatic acid phosphatase (PAP) linked to granulocyte-macrophage colony-stimulating factor (GM-CSF) 4.The final product, sipuleucel-T, is reinfused into the patient, inducing T-cell immunity to tumors that express PAP. Administer doses at ~2 week intervals for a total of 3 doses

Systemic Therapy

ADT (Androgen Deprivation Therapy)-Endocrine Therapy, Hormone Therapy Chemotherapy Ketoconazole +/- glucocorticoids Bone Metastasis: denosumab or zoledronate (or pamidronate)

GnRH Antagonist

Abarelix: serious life threatening hypersensitivity Degarelix (Firmagon): should not be given as IV; successful at suppressing testosterone levels

Effects of Mineralocorticoids

Active reabsorption of sodium and an associated passive reabsorption of water, as well as the active secretion of potassium in the principal cells of the cortical collecting tubule Hyperaldosteronism :hypertension and edema due to excessive Na+ and water retention; hypolakemia

Androgen Deprivation Therapy [ADT]

Also called "androgen ablation" and "castration" Medical ADT: LHRH agonist & LHRH antagonist Surgical ADT: bilateral orchiectomy LHRH analog and bilateral orchiectomy are equally effective. Addition of anti-androgens Testosterone level monitoring (<50ng/ml) Sometimes this therapy called "down staging" -" i.e. attempts to move a patient from stage IV to II

Abiraterone (Zytiga) DDI

An inhibitor of the hepatic drug-metabolizing enzyme CYP2D6

Prostate Volume

An ultrasound test used to estimate the size of your prostate.

Mitoxantrone (Novantrone) Properties

Anthracenedione (Anti-tumor antibiotic) Inhibition of topoisomerase II Free radical formation is much less than anthracyclines "Blue Bomb"

Sipuleucel-T (Provenge) MOA

Autologous cellular immunotherapy which stimulates an immune response against prostate cancer

Late S/Sx

Blood in urine usually with urinary obstruction Painful lymph nodes in the groin Impotence Pain in the hip, back, ribs Liver function test abnormalities Hallmark cancer symptoms

Cabazitaxel (Jevtana) Kinetics

CI with hepatic impairment (total bilirubin at greater than or equal to the upper limits of normal [ULN], or AST and/or ALT at least 1.5 × ULN).

Estramustine (Emcyt) Properties

Combination estrogen & alkylating agent An antimitotic agent (antimicrotubule agent)

Addition of Anti-Androgens

Combined androgen blockade (CAB) or total androgen blockade or maximal androgen deprivation •LH-RH analog +/- Anti-androgen ( 7days or more) •LH-RH analog +/-Anti-androgen +/- 5-alpha-reductase inhibitor (or finasteride or dutasteride)->triple androgen blockage: No data to support the triple blackage Definitive benefit •Antiandrogen therapy should precede or be co-administered with LHRH agonist and be continued in combination for at least 7 days for patients with overt metastases who are at risk of developing symptoms associated with the tumor flare in testosterone with initial LHRH agonist alone. CAB provides no proven survival benefit over single ADT Antiandrogen monotherapy appears to be less effective compared to medical or surgical castration and thus should not be recommended

Dutasteride (Avodart)

Current consensus: not recommending dutasteride for the indication to reduce prostate cancer risk The risk for more aggressive tumors outweighed the potential for chemoprevention. It makes it difficult to use of standard PSA cutoff points

First Line Therapy for High Risk Osteoporosis Pts

Denosumab (Prolia): 60 mg SQ every 6 months Zoledronate (Reclast) 5mg IV annually Alendronate 70mg PO weekly

Men with Castration-Recurrent Prostate Cancer w/ Bone Metastases

Denosumab (Xgeva) 120 mg SQ monthly (superior over zoledronate): Zoledronate (Zometa) 4mg IV Q3-4 weeks

DRE

Digital Rectal Exam Most cancers begin at the part of the gland that is in close proximity to the rectum Always used with PSA for appropriate diagnosis

Mitoxantrone (Novantrone) Adverse Rxns

Dose limiting myelosuppression GI - mild nausea and vomiting, diarrhea, mucositis(↓than anthracyclines) ↓ Cardiomyopathy, ↓↓↓ extravasation (↓than anthracyclines) Blue urine and blue sclera

Ketoconazole (Nizoral)

Dose related effect, inhibits steroidogenesis (both adrenal and testicular) reducing serum levels of testosterone and cortisol Inhibits many steroid dependent CYP-450 enzyme reactions May need to be combined with hydrocortisone Usually used for end-stage prostate cancer

REDEEM Trial

Dutasteride significantly reduced time to prostate progression compared to placebo Increased the percent of men with no detectable cancer Prostate cancer-related anxiety was reduced in the dutasteride arm compared to the placebo arm

Active Surveillance

Expectant management, watchful waiting Watch and Wait Therapy -Observation therapy

Ketoconazole (Nizoral) Adverse Rxns

Fatal hepatic dysfunction Gynecomastia Nausea/vomiting Rash May produce a disulfiram reaction

Finasteride (Proscar)

Finasteride prevents or delays the development of prostate cancer but it was associated w/ greater risk of high grade prostate cancer

Special Problems

Flutamide: worst for diarrhea, fatal liver dysfunction Bicalutamide: less diarrhea and hepatotoxicity Nilutamide: Interstitial pneumonitis, disulfiram-like reaction (no alcohol), delay in adaptation to the dark (watch for driving at night or through tunnels, may be delayed seconds to as much as 1-2 min) , CYP450 inhibitor (DDI with phenytoin, theophylline) DDI with warfarin (They displace coumarin anticoagulants, such as warfarin, from their protein-binding sites)

GnRH Analog MOA in Males

Following initial administration in males, the drug causes an initial increase in serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) values with subsequent increases in serum levels of testosterone. Chronic administration leads to sustained suppression of pituitary gonadotropins; testosterone serum levels consequently fall into the range normally seen in surgically castrated men at approximately 2 to 4 weeks after initiation of therapy. This leads to accessory sex organ regression.

Risk Factors

Gender: male Age: elderly Race: AA are at higher risk than any other races; thought to be due to higher levels of circulating testosterone Environment Diet: high fat diet -tissue active to create all cell signaling pathway; low zinc intake Genetics: first degree relative Smoking PIN (characterized by precancerous cellular proliferation in the prostate) is considered as a likely precursor of Prostate Cancer. BPH (characterized by cellular proliferation of prostatic stromal and epithelial cells) is NOT considered a precursor of Prostate Cancer.

Gleason Score

Grading of cancer cells Evaluation of the pattern of glandular differentiation Well differentiated = 1, poorly differentiated = 5 The higher the Gleason score, the more rapid the cancer is expected to spread Range is 1-5 by a primary and secondary system (two biopsy tissue samples) scores will range from 2-10

Anti-androgens Adverse Rxns

Gynecomastia Hot flashes Decreased libido Hepatitis Flutamide (most diarrhea), Bicalutamide (less diarrhea), Nilutamide (nausea or constipation)

Abiraterone (Zytiga) Adverse Rxns

Hypertension, Hypokalemia and Fluid Retention (joint swelling or discomfort, edema) due to Mineralocorticoid Excess Adrenocortical Insufficiency after an interruption of daily steroids and/or with concurrent infection or stress. Hepatotoxicity Food Effect: give on empty stomach (no food for at least 2 hour before and at least 1 hour after drug)

REDUCE Trial

Incidence of prostate cancer was reduced No significant difference for high grade prostate cancer: subjects in dutasteride arm have greater tendency for high grade prostate cancer Cardiac failure was higher in dutasteride groups

Chemotherapy

Infrequently used as cure is rare Systemic chemotherapy should be reserved for patients with castration-recurrent metastatic prostate cancer Docetaxel-based regimens are new standard care for the first-line treatment; more efficacious in neuroendocrine type advanced prostate cancer. If used, most common are: Docetaxel + Prednisone Cabazitaxel + Prednisone Mitoxantrone + Prednisone Docetaxel + Estramustine

Sipuleucel-T (Provenge) Adverse Rxns

Infusion reaction: Acute infusion reactions may occur within 1 day of infusion; the incidence of severe reaction may be higher with the second infusion, while the third infusion is associated with a decrease in the incidence of severe reactions. Fever, chills, hypertension, bronchospasm, dyspnea, tachycardia, flushing, joint or muscle pain, nausea, vomiting Premedicate with oral acetaminophen 650 mg and an antihistamine (eg, diphenhydramine 50 mg) ~30 minutes prior to infusion. Cerebrovascular events (stroke)

GnRH Analog Adverse Rxns

Initial tumor flares when the agent is started as testosterone production increases initially (prevented with anti-androgen therapy) ↑ Risk of Diabetes and Cardiovascular Disease Osteoporosis (prevented with bisphosphonate therapy [zoledronate, pamidronate, alendronate] or raloxifene or toremifene or denosumab) Hot flashes Impotence/decreased libido Gynecomastia/breast pain Pain at the site of injection Anemia in men (esp. as combined hormone blockade)

Estramustine (Emcyt) Misc. Information

Kept in the refrigerator (2-8 ºC) Milk, milk products, and calcium-rich foods or drugs (such as calcium-containing antacids) must not be taken simultaneously with estramustine Take with water at least 1 hour before or 2 hours after meals Estramustine may be poorly metabolized in patients with impaired liver function. Administer with caution.

Ketoconazole (Nizoral) Dose

Ketoconazole 400mg TID ± hydrocortisone

ADT & Osteoporosis

Men with ADT are at risk for osteoporosis Men with ADT are at risk for metabolic syndrome (HTN, DM, obesity, CV diseases). A baseline bone mineral density study should be considered. Supplemental Calcium 1200mg/day and Vitamin D3 (800-1000 ID daily) for all men over 50 y.o.

Cabazitaxel (Jevtana) Adverse Rxns

Neutropenia (dose limit): No Alopecia (complete): Yes N/V: Yes; diarrhea could be lethal Hypersensitivity: allergic rxns Cumulative fluid retention: not reported Premedication: diph, dexa, H2 Neurotoxicity: Yes; peripheral neuropathy Skin rashes/nail changes: not reported Cardiac conduction abnormalities: not reported (reported w/ peripheral edema, arrhythmia) Myalgia/arthralgia: Yes Compatibility w/ PVC bags: No Nephrotoxicity: Yes (hematuria, rarely renal failure)

Anti-androgens Properties

Nonsteroidal anti-androgens Inhibiting androgen uptake and/or inhibiting nuclear binding of androgen in target tissues (by binding to androgen receptors in the target tissue) Prostatic carcinoma is androgen-sensitive and responds to treatment that counteracts the effect of androgen Usually not used as a single therapy, may only be used for a short time (at least 7 days) and then discontinued. Sometimes combined with high doses of 5-α-reductase inhibitors Antiandrogen withdrawal phenomenon

Abiraterone (Zytiga)

Oral therapy in combination with prednisone is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC) who have received prior chemotherapy containing docetaxel. MOA:17 α-hydroxylase/C17,20-lyase (CYP17) inhibitor

PSA Density

PSAD The PSA level divided by the size of the prostate

PSA Velocity

PSAV Rate of PSA rise

PSA

Prostate Specific Antigen Produced by prostate epithelial cells Used for diagnosis and therapy monitoring Tends to increase with aging Annual prostate biopsy is recommended for disease progression because PSA kinetics may not be reliable as a monitoring parameter. PSA doubling time apprears unreliable for identification of progressive disease that remains curable High PSA needs further testing (biopsy) for diagnosis: Inconclusive cutoff: >4, >2.5

GnRH Antagonist Adverse Rxns

QT interval prolongation Less concern for allergic reactions Local injection site reactions were more frequent with degarelix LHRH antagonists rapidly and directly inhibit the release of androgens. Therefore, no "initial" flare is associated with these agents and no co-administration of antiandrogen is necessary

Recommended Duration of Initial Treatment

Short term ADT: 4-6 months Long term ADT: 2-3 years (preferred

Mitoxantrone (Novantrone) Dosing

Should be dose adjusted with elevated bilirubin With prednisone for its anti-androgen properties

GnRH Analog MOA in Females

Similar down-regulation of the pituitary gland by chronic exposure Suppression of gonadotropin secretion Decrease in serum estradiol to levels consistent with the postmenopausal state Reduction of ovarian size and function, reduction in the size of the uterus and mammary gland, as well as a regression of sex hormone-responsive tumors, if present. Goserelin is the only agent, indicated for breast cancer Goserelin and leuprolide are indicated for endometriosis

Sipuleucel-T (Provenge)

So called "prostate cancer vaccine" Autologous cellular immunotherapy indicated for the treatment of asymptomatic or minimally symptomatic metastatic hormone-refractory metastatic prostate cancer (increased mortality for several months) Recommended for asymptomatic or minimally symptomatic patients with ECOG 0-1. It is not recommended for patients with visceral disease (esp, hepatic metastases) and life expectancy < 6 months.

Effects of Glucocorticoids

Stimulation of gluconeogenesis Inhibition of glucose uptake in muscle and adipose tissue: a mechanism to conserve glucose. Stimulation of fat breakdown in adipose tissue

Radical/Partial Prostatectomy

TURP (transurethral resection of the prostatectomy) Open prostatectomy Partial prostatectomy: Open surgery to remove part of the prostate gland, leaving the posterior portion intact Radical prostatectomy: Open surgery to remove the entire prostate gland along with nearby tissues such as the seminal vesicles Pelvic lymph node dissection Efficacy of medical and surgical castration is same

SELECT Trial

The Selenium and Vitamin E Cancer Prevention Trial Selenium and/or Vitamin E increased ADRs, but did not reduce risk of the prostate cance

Clinical Pearls

The identity of the patient must be matched to the patient identifiers on the infusion bag and on the "Cell Product Disposition Form" prior to infusion A cell filter should NOT be used for administration. High cost

Estramustine (Emcyt) Adverse Rxns

Thrombosis (including fatal and nonfatal MI) Glucose intolerance Elevated blood pressure Hypersensitivity reactions (allergic reactions and angioedema) Hepatic function impairment Fluid retention/exacerbation of pre-existing peripheral edema Calcium/phosphorus metabolism disturbance Gynecomastia/impotence/decreased libido Carcinogenesis, Mutagenesis

Antiandrogen Withdrawal

Unknown mechanism: may have a stimulatory effect on mutated androgen receptors in prostate cancer cells In patients who have been receiving complete hormonal therapy and who show clear signs of disease refractory to this form of therapy that the first manipulation to be carried out should be withdrawal of the antiandrogen component of the complete hormonal therapy. However, patients who are receiving LHRH analogs for suppression of their testosterone should be maintained on this form of treatment. Always palliative and temporary (may respond 4-5 months after removal of the anti-androgen)

International Prostate Symptom Score

Used for BPH Sx Based on 7 questions of 0-5 scales per question.

Prostatic Acid Phosphatase

Used for diagnosis and therapy monitoring Elevated w/ tumor mass

Early S/Sx

Usually asymptomatic Weak urine stream Frequency Symptoms resemble those of BPH