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