Prostate Cancer

GnRH antagonist

Abarelix Degarelix (Firmagon)

Leuprolide

Lupron LHRH Analog

Mitoxantrone

Novantrone Anthracenedione (Anti-tumor antibiotic) Inhibition of topoisomerase II

Triptorelin

Trelstar LHRH Analog

Histrelin

Vantas LHRH Analog

LHRH analog Adverse Reactions

• tumor flare as the agent is started 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

Mitoxantrone (Novantrone) ADRs

Adverse Reactions • Dose limit is myelosuppression • GI - mild nausea and vomiting, diarrhea, mucositis(↓than anthracyclines) • ↓ Cardiomyopathy, ↓↓↓ extravasation (↓than anthracyclines) • Blue urine and blue sclera

Antiandrogens ADRs

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

Estramustine (Emcyt) ADRs

Adverse Reactions • 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

Ketoconazole ADRs

Adverse Reactions • fatal hepatic dysfunction • gynecomastia • nausea/vomiting • rash • may produce a disulfiram reaction

Sipuleucel-T (Provenge) ADRs

Adverse reactions • 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 (~4% stroke)

PC characteristics

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 (lumbar/sacral spine, pelvis, femur) • Most of patients may have hypercalcemia • Metastatic disease can also spread to the liver, lung, brain and adrenal glands

Bicalutamide

Casodex Antiandrogen

Sipuleucel-T (Provenge) Clinical pearls

Clinical pearls • For autologous use only; 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. Prior to infusion, inspect bag for signs of leaks (do not administer if leaking). Gently mix to resuspend contents; inspect for clumps or clotting; small clumps should disperse with the gentle mixing; do not administer if clumps remain. A cell filter should NOT be used for administration. • Infuse over ~60 minutes; infuse the entire contents of the bag. If infusion is interrupted, do not resume if bag is retained at room temperature for >3 hours. • High cost

PC Diagnosis

DRE (Digital Rectal Exam) • beginning at age 40-45 if at risk or 50 • most cancers begin at the part of the gland that is in close proximity to the rectum • always used with PSA for appropriate diagnosis PSA • Used for diagnosis and therapy monitoring • a half-life: 2-3 days • Tend to increase with aging • Annual Prostate biopsy is recommended for disease progression because PSA kinetics may not be reliable as 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 • >1 • PSA velocity (PSAV): Rate of PSA rise • PSA density (PSAD): The PSA level divided by the size of the prostate. • Prostate volume: An ultrasound test used to estimate the size of your prostate. • International Prostate Symptom Score • Prostatic Acid Phosphatase (PAP)

Ketoconazole DDI

Drug Interactions • requires acid environment for dissolution and absorption (PPI's, H2-blockers, antacids, sucralfate) • inhibits CYP3A4 & has major drug interactions

Cabazitaxel (Jevtana) DDI

Drug interactions • Substrate of CYP3A4 (like paclitaxel and docetaxel)

Prostate cancer S/Sx

Early • usually asymptomatic • weak urine stream • frequency • symptoms resemble those of BPH Late • 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

Estramustine

Emcyt Combination estrogen & alkylating agent antimitotic agent Take with water at least 1 hour before or 2 hours after meals.

Flutamide

Eulixin Antiandrogen

Active Surveillance

Expectant Management, watchful waiting Watch and Wait Therapy (Observation Therapy) Advantage: QOL is good, bc avoid toxicity of treatment agents. Disadvantage: when try to treat cancer later may have lost the right timing. Use for Very Low, Low, or Intermediate Recurrence Risk of Prostate Cancer

Degarelix

Firmagon GnRH antagonist

Antiandrogens

Flutamide (Eulixin) Bicalutamide (Casodex) Nilutamide (Nilandron)

Abareliz

GnRH antagonist

Abarelix

GnRH antagonist • Should be reserved for advanced prostate cancer with no alternative therapy • Serious life-threatening hypersensitivity

Degarelix (Firmagon)

GnRH antagonist • successful at suppressing testosterone levels within three days and was maintained • local injection site reactions were more frequent with degarelix • no systemic allergic reactions were reported • GnRH antagonists should not cause tumor flare.

LH-RH or GnRH analogs

Goserelin (Zoladex) Leuprolide (Lupron) Triptorelin (Trelstar) Histrelin (Vantas)

Chemotherapy in PC

Infrequently used as cure is rare • Systemic chemotherapy should be reserved for patients with castration-recurrent metastatic prostate cancer except when studied in clinical trials. • Many combinations have been tried • Docetaxel-based regimens are new standard care for the first-line treatment. More efficacious in neuroendocrine type advanced prostate cancer. If used the most common are; • Docetaxel + Prednisone Preferred by NCCN (every three weeks) • Cabazitaxel + Prednisone • Mitoxantrone + Prednisone • Docetaxel + Estramustine

Cabazitaxel

Jevtana antimitotic activity - Promote microtubule assembly and interfere with disassembly, forming tubulin polymerization, decreasing cell division - Inhibitor of angiogenesis In combination with prednisone Substrate of CYP3A4

Salvage Hormone Therapy

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

Cabazitaxel (Jevtana) Kinetics

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).

Abiraterone (Zytiga) MOA

Mechanism of action 17 α-hydroxylase/C17,20-lyase (CYP17) inhibitor

Sipuleucel-T (Provenge) MOA

Mechanism of action Autologous cellular immunotherapy which stimulates an immune response against prostate cancer.

Cabazitaxel (Jevtana) MOA

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

Estramustine (Emcyt)

Miscellaneous • Kept in the refrigerator • 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.

Nilutamide

Nilandron Antiandrogen

Ketaconazole

Nizoral Inhibits CYP3A4 Taken with hydrocortisone Take on empty stomach, avoid PPI's, H2-blockers, antacids, sucralfate, need acidic environment for dissolution

Dutasteride (Avodart)

Not recommending dutasteride for the indication to reduce prostate cancer risk • The risk for more aggressive tumors outweighed the potential for chemoprevention. • It makes difficult to the use of standard PSA cutoff points • Incidence of prostate cancer was reduced • Subjects in dutasteride arm have greater tendency for high-grade prostate cancer • Cardiac failure was higher in dutasteride groups

Abiraterone (Zytiga) Use

Oral therapy (1,000 mg PO QD) in combination with prednisone (5 mg PO BID) is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC) who have received prior chemotherapy containing docetaxel.

Mitoxantrone (Novantrone)

Properties • Anthracenedione (Anti-tumor antibiotic) • Inhibition of topoisomerase II • Free radical formation is much less than anthracyclines better safety • so called "Blue Bomb"

Antiandrogens Properties

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

LHRH MOA

Properties (Mechanism of Actions) 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. 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 is indicated for endometriosis

Sipuleucel-T

Provenge

Prostate Cancer Risk Factors

Risk factors • Gender: Male • Age: Elderly • Race: Blacks are at a higher risk than any other race, thought to be due to higher levels of circulating testosterone (African-Americans > Caucasian >Asians, native Americans) • Environment Workers exposed to batteries with cadmium Rubber or farm workers • Diet: High fat diet, Low zinc intake (zinc is antagonized by many chemicals and is found in very high concentrations in prostatic tissue and is involved in DNA and RNA repair and synthesis) • Genetics: first degree relative, oncogene mutation • Smoking • PIN (Prostatic intraepithelial neoplasia)

Selenium and Vitamin E Cancer Prevention

Selenium and/or Vitamin E increases ADRs, but did not reduce the prostate cancer

Antiandrogens Problems

Special Problems • Flutamide: worst for diarrhea, fatal liver dysfunction • Bicalutamide: less diarrhea and hepatotoxicity high (96%) protein binding • Nilutamide: Interstitial pneumonitis, disulfiram-like reaction (no alcohol), Delay in adaptation to the dark (watch 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)

Sipuleucel-T (Provenge) Steps

Steps: 1. Peripheral blood is collected (~3 days prior to infusion) 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 (also termed PA2024), composed of an antigen specific for prostate cancer, prostatic acid phosphatase (PAP) linked to granulocyte-macrophage colony-stimulating factor (GM-CSF) and cultured for ~40 hours. 4. The final product, sipuleucel-T, is reinfused into the patient, inducing T-cell immunity to tumors that express PAP. a. Each dose contains ≥50 million autologous CD54+ cells (obtained through leukapheresis) activated with PAP-GM-CSF

Goserelin

Zoladex LHRH Analog

Abiraterone

Zytiga 17 α-hydroxylase/C17,20-lyase (CYP17) inhibitor Inhibit CYP2D6, Substrate of CYP3A4 Taken with prednisone Take on empty stomach

Ketoconazole dose

ketoconazole 400mg tid ± hydrocortisone

Sipuleucel-T (Provenge)

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 and life expectancy < 6 months.

Mitoxantrone (Novantrone)

should be dose adjusted with elevated bilirubin • with prednisone for its anti-androgen properties

Finasteride (Proscar) Prevention

• 5-alpha reductase inhibitors: inconlusive so far. finasteride prevented or delayed the development of prostate cancer, but it was associated with greater risk of high-grade prostate cancer

Estramustine (Emcyt)

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

Gleason Score

• Grading of cancer cells • Evaluation of the pattern of glandular differentiation • well differentiated = 1, poorly differentiated = 5 • The higher the Gleason 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

Abiraterone (Zytiga) ADRs

• 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)

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

Prostate Cancer

• In most cases, very slow growing tumor (rare cases of fast growing tumor were reported) • Metastatic disease is incurable • Nerves near the prostate are involved in erection thus surgical procedures involving the prostate often result in impotence. • Most of the lymphatic vessels lead to the pelvic lymp nodes. • The growth of the gland is hormone regulated. • Testosterone is converted to DHT (dihydrotestosterone) in the prostate by 5α-reductase (i.e., finasteride, dutasteride). • DHT is potent and is the primary androgen affecting normal and cancer cell growth, it has also been demonstrated to inhibit apoptosis.

Cabazitaxel (Jevtana) ADRs

• Neutropenia (dose limit): No ∆ duration of infusion • Alopecia complete • N/V, diarrhea could be lethal • hypersensitivity: allergic rxns • premedication: Diph, Dexa, H2 • neurotoxicity: peripheral neuropathy • myalgia, arthralgia • PVC compatible: NO • Nephrotoxic: hematuria, rarely renal failure

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

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 o Hyperaldosteronism Hypertension and edema due to excessive Na+ and water retention. Hypokalemia

Abiraterone (Zytiga) DDI

• an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6