Prostate Cancer
LHRH agonists available for PC: Goserelin (Zoladex)
3.6mg SQ q 4 weeks 10.8mg SQ q 12 weeks
LHRH agonists available for PC: Triptorelin (Trelstar)
3.75mg IM q 4 weeks 11.25mg IM q 12 weeks 22.5mg IM q 24 weeks
Prostate cancer progression
5 year relative survival rate is 97.5% which means PC is a slow growing, indolent disease for most patients
LHRH agonists available for PC: Histrelin (Vantas)
50mg SQ implant q 12 months
LHRH agonists available for PC: Leuprolide (Lupron IM, Eligard SQ)
7.5mg IM/SQ q 1 month 22.5mg IM/SQ q 3 months 30mg IM/SQ q 4 months 45mg IM/SQ q 6 months 65mg SQ q 12 months
CRPC 1st line Treatment Options Docetaxel (Taxotere) Dosing and ADEs
75mg/m2 IV q 3 weeks + prednisone 5mg PO BID • ADE: myelosuppression, alopecia, edema, peripheral neuropathy, hypersensitivity reaction • Caution with hepatic impairment! Avoid use if Tbili > ULN, or AST and/or ALT >1.5 times ULN concomitant with alkaline phosphatase >2.5 times ULN
Castration Resistant Prostate Cancer (CRPC)
= serum testosterone <50ng/dL and disease progression (AKA, at goal but had disease progression) Patients may have been on an ADT and so the NCCN makes recommendations about treatment
Castrate naïve (sensitive) Metastatic (any T, any N, M1)
Initial therapy should be Continue ADT plus: • Abiraterone Acetate or • Enzalutamide or • Apalutamide or • docetaxel x 6 cycles
Nilutamide BBW for PC
Interstitial pneumonitis so once a patient is on this, you have to do a PFT at baseline and periodically
Pathologic T staging criteria FYI
T2 Organ confined T3 Extraprostatic extension T3a Extraprostatic extension or microscopic invasion of bladder neck T3b Tumor invades seminal vesicle(s) T4 Tumor is fixed or invades adjacent structures other than seminal vesicles (ex. rectum, bladder, pelvic wall) notice, there is no T1 in pathological staging
What is a Gleason Score?
• Describes how cancer cells look like under a microscope • Pathologist looks at biopsy sample and assigns a score to the most predominant pattern and assigns a score to second most predominant pattern
PSA normal ranges
• Normal range of PSA < 4ng/mL; though some patients between 2.5 and 4 will have prostate cancer -Levels are not definitive of the presence of PC, we want to check PSA velocity too. PSA velocity may be another predictor of prostate cancer risk. • Estimated greater than 67% chance of prostate cancer for PSA > 10
Screening Guidelines American Cancer Society recommends routine screening for: - Men age 50+ with intermediate risk of prostate cancer
- Men age 50+ with intermediate risk of prostate cancer - Men age 45+ with high risk of prostate cancer (includes African Americans and those with a first-degree relative diagnosed before age 65) - Men age 40+ those with more than one first-degree relative diagnosed before age 65
2018 US Preventative Service Task Force recommendations on prostate cancer screening:
- Men: 55 - 69 yo: routine screening should be individualized with risks/benefits explained to the patient (between pt and dr) - Men: 70+ yo: routine screening not recommended
What does M1 mean in PC
- Patients are classified as M0 = No distant metastasis M1 = Distant metastasis M1a = Nonregional lymph nodes M1b = Bones M1c = Other sites with or without bone disease so this patient is distant metastasis
Prostate cancer epidemiology
-2nd most commonly diagnosed cancer in the US -Most common cancer in men -Prostate cancer represents 13.1% of all new cases of cancer in the US
Prostate cancer breakdown by stage
-74% of cases are localized (confined to primary site which is the prostate) -13% of cases are regional (spread to regional lymph nodes) -7% is distant (cancer has metastasized.) -6% unknown
How does race/ethnicity play into Prostate Cancer risk
-African American men had higher risk of developing (18.2% vs. 13.3%) and dying from (4.4% vs. 2.4%) prostate cancer compared to Caucasian American men - Less common in Asian Americans - Incidence higher in the US and Scandinavian countries
Which 2 second generation anti-androgens have seizure risk?
-Apalutamide and Enzalutamide. So for these, if they have a risk of seizure, history or seizure, or having ongoing seizures, avoid use however, darolutamide does not have the seizure risk! So if a patient is at risk for developing seizures at baseline, put them on this vs the others.
Metastatic CRPC - 1st line Treatment Options Visceral Metastases
-Docetaxel + Prednisone (category 1) -Enzalutamide (category 1) Alternatives: -Abiraterone + Prednisone -Alternative chemo (mitoxantrone) -Secondary hormonal therapy* (ex. antiandrogen, antiandrogen withdrawal, ketoconazole, or CS) Remember, the secondary hormonal agents are not really recommended by the NCCN. Category 1 is 1st line
Metastatic CRPC - 1st line Treatment Options NO Visceral Metastases
-Enzalutamide (category 1) -Abiraterone + Prednisone (category 1) -Docetaxel + Prednisone (category 1) -Radium-223 for symptomatic bone metastases (category 1) -Sipuleucel-T for asymptomatic or minimally symptomatic patients -Secondary hormonal therapy* Remember, the secondary hormonal agents are not really recommended by the NCCN. Category 1 is 1st line
How does family history play into Prostate Cancer risk
-Familial predisposition may be responsible for 5-10% of cases • BRCA-2 mutations associated with 2-6 fold increase in risk for pc • Lynch syndrome associated with 2-5 fold increase in risk for prostate cancer • Lifetime risk of prostate cancer is 16% if one first degree relative is affected vs 8% if no family history
When indicated for general osteoporosis/bone loss, different dosing and formulation used: supportive care in PC
-If it is for treatment of androgen deprivation-induced bone loss: Denosumab (Prolia) SQ: 60 mg Q6 months -For Osteoporosis: Zoledronic acid (Reclast): 5mg IV once a year
What are the risk factors for prostate cancer
-Race/ethnicity -age -family history
Describe each stage in the Gleason score in PC
1 = nearly normal cells 2 = some abnormal cells loosely packed 3 = many abnormal cells 4 = very few normal cells left 5 = completely abnormal cells
For M0, CRPC, what agents do we like the best
2nd gen anti-androgen or androgen metabolism inhibitor Do not really use ketoconazole or CS much because the NCCN doesn't recommend
Apalutamide (Erleada) • MOA
2nd generation anti-androgen nonsteroidal androgen receptor inhibitor; apalutamide binds directly to the androgen receptor ligand-binding domain to prevent androgen-receptor translocation, DNA binding, and receptor-mediated transcription - Androgen receptor inhibition results in decreased proliferation of tumor cells and increased apoptosis, leading to a decrease in tumor volume
Enzalutamide (Xtandi) • MOA:
2nd generation anti-androgen pure androgen receptor signaling inhibitor; inhibits androgen receptor nuclear translocation, DNA binding, and coactivator mobilization, leading to cellular apoptosis
Darolutamide (Nubeqa) • MOA:
2nd generation anti-androgen competitive androgen receptor(AR) inhibitor. It also inhibits AR translocation and AR-mediated transcription. AR inhibition results in decreased proliferation of prostate tumor cells and increased apoptosis, leading to a decrease in tumor volume
PC: characteristics of Favorable intermediate:
: Either T2b-T2c OR PSA 10-20 + Grade Group 1 or 2 + <50% biopsy cores positive
Example characteristics of low risk PC
: T1-2a, T1-2a and Grade Group 1 and PSA < 10
Example characteristics of very low risk PC
: T1c, Grade Group 1, PSA < 10, < 3 Biopsy cores positive with ≤ 50% cancer in any one core, and PSA density < 0.15 ng/mL/g
PC: characteristics of Unfavorable intermediate:
: T2b to T2c, Grade Group 3, PSA 10-20, ≥ 50% biopsy cores positive for cancer
Antiandrogens for PC ADEs and Monitoring
ADE: Diarrhea, gynecomastia, elevated LFTs, hot flashes Before putting patients on this class, you have to do LFT, serum testosterone, PSA, and PFT before starting Monitoring: LFTs monthly x 4 (then periodically), serum testosterone, PSA, pulmonary function (nilutamide)
CRPC 1st line Treatment Options Abiraterone (Zytiga, Yonsa) • Dosing and ADEs
ADE: diarrhea, edema, hypokalemia, hypertension, hepatotoxicity, hypertriglyceridemia • Given with steroids (either prednisone 5mg twice daily or methylprednisolone 4mg twice daily depending on formulation) to minimize signs of mineralocorticoid excess from treatment - Steroid increases the risk of hyperglycemia and may worsen or induce diabetes • Monitoring: LFTs, potassium and phosphate levels, blood pressure on monthly basis
Second-line Therapies for CRPC: Cabazitaxel (Jevtana) Dosing and ADEs
ADE: febrile neutropenia, hypersensitivity reaction, mucositis, edema, peripheral neuropathy Pretreat for hypersensitivity reaction Neuropathy is a common reason why a patient may D/C Dose: 20mg/m2 IV q3 weeks in combo with prednisone -25mg/m2 IV every 3 weeks can be considered in select patients favoring aggressive approach BUT: 20mg/m2 had less toxicity (febrile neutropenia, diarrhea, fatigue); non-significantly shorter PFS and overall survival compared to 25mg/m2
Difference between active surveillance and observation for PC treatment
Active surveillance means to take an active approach to managing PC, not doing anything but monitoring the patient incase the disease progresses in which we would then put them on treatment vs Observation is more passive management.; we leave them to be on their own and once they start having symptoms, then you decide whether you want to put them on AS or treat them
LHRH agonist adverse effects (counsel patients on it)
Acute: Tumor flare, gynecomastia, hot flashes, ED, edema, injection site reaction Long-term: Osteoporosis, clinical fracture, obesity, insulin resistance which increases the risk of diabetes, CV events, alteration in lipids
Clinical presentation of advanced disease in Prostate cancer
Advanced means the cancer has spread to other organs and sxs may be related to the site it spread to • Back pain • Cord compression • Lower-extremity edema • Pathologic fractures • Anemia • Weight loss
CRPC 1st line Treatment Options Radium-223 (Xofigo) • MOA:
Alpha-emitting radiopharmaceutical, causes double strand DNA breaks, resulting in an antitumor effect on bone metastases we use alpha particles because they have a range of <100 micrometers which limits the damage to surrounding tissues while targeting the prostate tumor
2nd line therapy for CRPC?
Assuming you were put on tx and they had a disease recurrence or disease spread, you decide whether the patient had prior treatment with docetaxel or enzalutamide or abiraterone. If prior docetaxel, give abiraterone + prednisone or Enzalutamide since those are NCCN category 1. If they got prior enzalutamide or abiraterone and they relapsed, consider docetaxel If they have micro cellulite MSSA high or DNA mismatch repair (DMMR) or TMB 10 or higher, consider pembrolizumab for either prior treatment. Once a patient has any of these mutations or disease markers, consider the specific agent listed.
Degarelix (Firmagon) for PC MOA
Binds reversibly to GnRH receptors on cells in pituitary gland, dramatically reducing LH/FSH and reducing production of testosterone to castrate levels
What does N0 mean in PC
Both clinical and pathologic staging define NX: regional lymph nodes as not assessed N0:Negative; No positive regional nodes N1:Positive; Metastases in regional nodes So this patient is node negative "NO (N0) node"
What does castration sensitive mean in PC?
Castration naïve means we don't know whether the patient will respond to the hormonal agents we may give. Once a patient has metastasis (AKA high risk is diagnosed), we normally do a combined ADT with either Abiraterone or docetaxel. Above combo is used in patients that are either: 1. metastatic (w/o starting tx AKA castration naïve) OR 2. Those who started tx and got to testosterone goal of <50 ng/dl and have disease recurrence.
Castration Sensitive Prostate Cancer
Combined modality approach as initial therapy for Castration Sensitive (or Naïve) Prostate Cancer for select high risk and metastatic patients: • ADT + Abiraterone - For High risk = defined as: 2 of the following 3 factors: Gleason > 8, three bone lesions, measurable visceral disease • ADT + Docetaxel x 6 cycles - For High volume patients = defined as: presence of visceral metastases, and/or 4 bone metastases
Secondary Hormonal Therapies for Non-metastatic castrate resistant prostate cancer (M0 CRPC)
Continue ADT to maintain castrate levels of testosterone and add: (one of these) • Second-generation antiandrogen: -Apalutamide (for M0) -Enzalutamide* (for M0 and M1) -Darolutamide (for M0) • Can consider Androgen metabolism inhibitor: Abiraterone* with prednisone or methylprednsiolone (for M1 CRPC) • Ketoconazole + hydrocortisone • CS (hydrocortisone, prednisone, dexamethasone)
Staging System for PC: Tumor (T)
DRE is the doctors estimate on disease extent and is based on the PE results including TRUS, biopsy, and imaging. For patients who had since removed their prostate, doctors can determine their pathologic T (which is likely to be more accurate than the clinical T since they examine it in the lab after it is removed).
Why do we do combo androgen blocking for PC patients?
Especially for patients who don't have metastatic disease, the reason is because normally PC cells are hormone independent cells which means that whether testosterone levels decrease or not, the cells continue to grow. This hormone independent growth is the reason for relapse in most patients. Relapse in 2-4 years post starting treatment so we want to achieve more of a blockade (or decrease the testosterone levels in the body) Also remember that testosterone can be produced by estraesticuluar androgens
Intermediate Risk for PC: Favorable Intermediate
Expected Survival < 10 years: initial therapy should be Observation (preferred), Alternative: -[External Beam Radiation Therapy] or -[brachytherapy] Expected Survival 10 years or more: initial therapy should be either -AS alone -External Beam Radiation Therapy alone -brachytherapy alone or -[Radical Prostatectomy ± pelvic lymph node dissection] (± EBRT ± ADT if adverse features or positive lymph nodes)
Recurrence Risk low for PC
Expected Survival: < 10 years, initial therapy should be Observation Expected Survival: 10 years and up: Initial therapy should be AS (preferred), Alternatively: 1, 2, or 3 1. External Beam Radiation Therapy 2. brachytherapy, or 3. Radical Prostatectomy (± EBRT ± ADT if adverse features)
Recurrence Risk Very low for PC (and low risk)
Expected Survival: < 10 years, initial therapy should be Observation Expected Survival: 10-19 years: initial therapy should be Active Surveillance Expected Survival: > 20 years: Initial therapy should be AS (preferred), Alternatively: 1, 2, or 3 1. External Beam Radiation Therapy 2. brachytherapy, or 3. Radical Prostatectomy (± EBRT ± ADT if adverse features)
Intermediate Risk: Unfavorable Intermediate for PC
Expected Survival: < 10 years; initial therapy should be Observation (preferred) Alternative: 1. [EBRT + ADT ] or 2. [EBRT + brachytherapy ± ADT] Expected Survival: 10 years and up; initial therapy should be; 1, 2, or 3 1. RP ± pelvic lymph node dissection (± EBRT ± ADT if adverse features or positive lymph nodes) 2. EBRT + ADT 3. EBRT + brachytherapy ± ADT
• ADT + Abiraterone Indication in PC
For high risk patients with castration sensitive PC. - High risk defined as: 2 of the following 3 factors: Gleason > 8, three bone lesions, measurable visceral disease -Prolongs overall survival and secondary endpoints in patients with high risk castration-sensitive PC
• ADT + Docetaxel x 6 cycles indications in PC
For patients who are metastatic (with high volume disease) and are castration sensitive. - High volume defined as: presence of visceral metastases, and/or 4 bone metastases - Improves progression-free and overall survival in men with metastatic castration-sensitive PC compared with ADT alone - This increased efficacy is also associated with an increase in serious toxicity
Difference in bone products for PC supportive care
For patients with bone metastasis, we check if they have OP. Because ADT causes a loss of BMD, we may also give them a bone modifying agent to prevent androgen deprivation induced bone loss in PC. If a patient has OP, reclast is given Different doing for zoledronic acid whether it is used for bone modifying in metastasis vs preventing ADT induced bone loss
Prostate cancer survival by stage
For patients with localized/regional disease, PC is a slow growing indolent disease (both have 100% 5yr survival rate) vs those with distant (metastatic disease) which has a 5yr survival rate of 31% aka metastatic has worse outcomes which makes sense
Androgen Deprivation Therapy for PC
Gold Standard for advanced PC and has 2 methods: 1. Surgical castration = bilateral orchiectomy (removal of the testes) 2. Medical castration (either) - LHRH agonists +/- antiandrogen - LHRH antagonist Note: LHRH is also known as gonadotropin releasing hormone (GnRH)
2 most common used LHRH agonists in PC
Goserelin or leuprolide
CRPC 1st line Treatment Options Radium-223 (Xofigo) Inidcation
Indicated for castration resistant PC in patients with symptomatic bone metastases and no visceral metastases prior to and after docetaxel therapy • Not used in combination with chemotherapy • Administered IV once a month for 6 months • SEs: Peripheral edema, nausea, myelosuppression
Castrate resistant (serum testosterone levels less than 50 mg/dl) Metastatic (any T, any N, M1) If small cell or neuroendocrine
Initial therapy should be Chemotherapy • Cisplatin/etoposide • Carboplatin/etoposide • Docetaxel/carboplatin • Cabazitaxel/carboplatin Best supportive care
Regional (any T, N1, M0) Expected survival: ≤ 5 years and asymptomatic
Initial therapy should be Observation or ADT
High (T3a or Grade 4 or 5 or) PSA > 20 or Very High (T3b-T4, Primary Gleason pattern 5, or >4 cores with Grade Group 4 or 5) expected survival being MORE THAN 5 years OR SYMPTOMATIC:
Initial therapy should be either • EBRT + 1.5-3y ADT (Category 1) ± docetaxel (Category 1 for very high risk only) • EBRT + brachytherapy + 1-3y ADT (ADT category 1) • RP + pelvic lymph node dissection (± EBRT ± ADT if adverse features or positive lymph nodes)
Regional (any T, N1, M0) Expected survival: >5 years or symptomatic
Initial therapy should be either: • ADT + EBRT (preferred) • ADT+ EBRT+ abiraterone (or fine-particle abiraterone, category 2B) • ADT • ADT + abiraterone (or fine-particle abiraterone, category 2B)
Castrate resistant (serum testosterone levels less than 50 mg/dl) Metastatic (any T, any N, M1) If Adenocarcinoma
Initial therapy should be to continue ADT plus: • Abiraterone (category 1) • Docetaxel x 6 cycles (category 1 • Enzalutamide (Category 1) • Sipuleucel-T • Radium-223 • Other hormonal therapy
Castrate resistant (serum testosterone levels less than 50 mg/dl) Recurrent (any T, any N, M0)
Initial therapy should be to continue ADT plus: • PSADT > 10 months: Monitoring or secondary therapy • PSADT ≤ 10 months: Apalutamide or Darolutamide or Enzalutamide or secondary therapy
Why do we use Cabazitaxel as 2nd line after prior docetaxel use in PC?
It has Poor affinity for multidrug resistance (MDR) proteins, therefore conferring activity in resistant tumors; has activity in docetaxel resistance! Advantage over docetaxel is that it still has activity against docetaxel resistant tumor cells which is why it is not normally used as 1st line but as 2nd line instead after prior docetaxel. Once a patient has responded to docetaxel and then relapsed, consider this.
Gleason score groups
Low Grade: Group 1: Gleason score of 6 or less Intermediate favorable: Grade Group 2: Gleason score of 7 (3 + 4) Intermediate unfavorable: Grade Group 3: Gleason score of 7 (4 + 3) High Grade: Group 4: Gleason score of 8 High Grade: Group 5: Gleason score of 9-10
Clinical pearls with abiraterone for CRPC
May have lots of interactions, so run a DDI before putting patients on this! Since this is always given with a steroid, and it is daily administration, we have to check blood glucose periodically! The patient is going to be at increased risk for hyperglycemia and it could induce DM. Counsel patients to look for s/s of DMs and avoid this drug if the patient has DM.
LHRH Agonists Initial disease flare
Normally increases testosterone and for patients who have bone metastasis, we see an increase in bone pain for those without bone metastasis, we see symptoms correlated to the spot of primary cancer ex) urinary symptoms
Bone is most common site for prostate cancer metastases; supportive care
Once it metastasizes to bone, they have an increase in skeletal related events compression fractures, and pathologic fractures (which may be asymptomatic). -We give a bone modifying agent (ex. zometa) because it was shown to decrease the risk (prevent) of SRE and has a possible antitumor effect - Zoledronic acid (Zometa) 4mg IV Q3-4 weeks (Q12 weeks can also be used); -dose adjust for renal impairment OR - Denosumab (Xgeva) 120mg SQ every 4 weeks
Darolutamide (Nubeqa) Dosing and ADEs
Only indicted for non-metastatic castration resistant PC 600 mg BID with food - Renal dose adjustment • CrCl 15-29 ml/min: 300mg BID • CrCl <15 m?/min: Not studied • ADEs: Fatigue, hypertension, rash
PSA velocity for prostate cancer
PSA velocity is a change in the PSA level over time. -If PSA velocity is >0.35 ng/ml per year, that indicates a high risk of developing PC compares to those with a level 0.35 or below per year. Because PSA is not limited to PC, patients prostatitis may also dramatically increase their PSA velocity which confounds the interpretation that low levels of PSA and PSA velocity may indicate low risk but are not definite markers
Treatment Options for Non-Metastatic Castrate Resistant PC: PSA doubling time
PSADT is an indicator of biochemical or clinical progression. You look at the PSA level at baseline and if the PSA level doubles within less than 10 months, it means the patient has a PSA that is aggressively increasing. For such patients, if they are castration resistant and don't have metastasis, and they are on ADT alone, you may consider adding Apalutamide, Enzalutamide, Darolutamide, or other secondary hormone therapies although the secondary agents are not commonly recommended
Second-line Therapies: Depends on which agent used first Prior Docetaxel (for CRPC?)
Preferred: -Abiraterone with prednisone (category 1)* -Enzalutamide (category 1)* -Cabazitaxel* or cabazitaxel/carboplatin Alternatives: -Pembrolizumab for MSI-H, dMMR , TMB≥10 -Mitoxantrone -Radium-223 for bone metastases -Sipuleucel-T -Other secondary hormone therapy
Second-line Therapies: Depends on which agent used first Prior Enzalutamide or Abiraterone (for CRPC?)
Preferred: -Docetaxel (category 1)* -Sipuleucel-T* -Olaparib for HRR (category 1) Alternative: -Cabazitaxel/carboplatin -Pembrolizumab for MSI-H, dMMR , TMB≥10 -Radium-223 for bone metastases -Rucaparib for BRCAm -Abiraterone + prednisone or dexamethasone -Enzalutamide -Other secondary hormone therapy
CRPC 1st line Treatment Options Docetaxel (Taxotere) • MOA
Promotes assembly of microtubules from tubulin dimers and inhibits depolymerization of tubulin which stabilizes microtubules in the cell • Results in inhibition of DNA, RNA and protein synthesis
Apalutamide (Erleada) Dosing and ADEs
Remember, this is approved only for NON-metastatic castration resistant PC 240 mg orally once daily ADE: fatigue, HTN, rash, diarrhea, nausea, arthralgias, fracture risk, falls, peripheral edema • SEIZURE occurred in 0.2% of patients!! Permanently D/C if patient develops a seizure during tx
Treatment Options for Non-Metastatic Castrate Resistant PC: If castration resistant but no metastases (M0 no distant metastasis)
Step 1: If castration resistant but no metastases, apalutamide, Enzalutamide, darolutamide or other secondary hormonal therapies can be used Step 2: Continue ADT to maintain castrate testosterone (<50ng/dL) Step 3: Observation if PSA doubling time is >10 months -Apalutamide, if PSADT is 10 months or less (Category 1) -Enzalutamide if PSADT is 10 months or less (Category 1) -Darolutamide if PSADT UNDER 10 months (Category 1) -Other secondary hormonal therapies if PSADT is 10 months or less (Category 1)
T Criteria in PC (T2 through T4) (FYI but including for completeness sake)
T2: Tumor is palpable and confined to prostate T2a: Tumor involves one-half of one side or less T2b: Tumor involves >half of one side but not both sides T2c: Tumor involves both sides T3: Extraprostatic tumor that is not fixed or does not invade adjacent structures T3a: Extraprostatic extension (unilateral or bilateral) T3b: Tumor invades seminal vesicle(s) T4: Tumor is fixed or invades adjacent structures such as external sphincter, rectum, bladder, levator muscles, and/or pelvic wall
T Criteria in PC (TX through T1c) (FYI but including for completeness sake)
TX = Primary tumor cannot be assessed T0 = No evidence of primary tumor T1 = Clinically apparent tumor; not palpable T1a = Tumor incidental histologic finding in <5% of tissue reacted T1b = Tumor incidental histologic finding in >5% of tissue reacted T1c = Tumor identified by needle biopsy but not palpable
Why do we use ADT for castration sensitive PC
Testosterone drives the growth of PC cells. Once we deprive the cancer ells of testosterone, we are bound to slow down the growth and have better control of the cancer
For castration sensitive and resistant PC, what does that mean
These categories are for patients who had treatment with response and disease came back or it spread to other areas. Distinguish if the patient had a level of testosterone that was at goal and after that determine if the PSA is increasing or not which will tell you between metastatic and recurrent disease Those with PSA recurrence alone may not need treatment
Enzalutamide (Xtandi) Dosing and ADEs
Unlike apalutamide, Enzalutamide is approved for BOTH metastatic and non-metastatic castration resistant PC 160mg PO daily with or without food -Reduce dose to 80mg QD (if given with strong CYP 2C8 inhibitors) -Increase dose to 240 mg QD (if given with strong CYP 3A4 inducers) • Steroids not required • ADE: diarrhea, fatigue, headache, myalgias, edema, SEIZURE (occurred in 2.2% w predisposing risk factors)
When we look at treating metastatic CRPC, it depends on if they have visceral or not, what does that mean?
Visceral metastasis is when a patient has metastasis in the lung, liver, brain or intestine
First degree relative means
a parent, siblings or children with the disease
Secondary Hormonal Therapies for Non-Metastatic CRPC
basically, ADT + 2nd gen Antiandrogen
Most common site of prostate cancer metastasis is
bone, lung, liver, brain, and adrenal glands
High risk group of gleason score correlates to
cells looking completely ABnormal: correlates to a score of 8 and up indicates a HIGHER risk of progression/recurrence
Low risk group of gleason score correlates to
cells looking normal: correlates to a score of 6 or less indicates a LOWER risk of progression/recurrence
Castration Resistant Prostate Cancer (CRPC) NCCN recommendations
continue ADT and maintain castrate levels (testosterone <50) while adding other therapies • Can consider Secondary hormonal therapies can be used for M0 and M1 disease; AKA castration resistant w/o distant metastasis or those with distant metastasis in addition to them being castration resistant • For asymptomatic or minimally symptomatic metastatic patients without liver metastases, ECOG 0-1, > 6 mo life expectancy - Sipuleucel-T is a 1st line option • 1st line systemic agent (or following Sipuleucel-T if used as 1st line) is based on absence/presence of visceral metastases
FSH
follicle-stimulating hormone
Antiandrogens for PC MOA:
inhibits androgen uptake and/or binding of androgen in target tissues; specifically a competitive inhibitor for the binding of dihydrotestosterone and testosterone AKA: once you have this competitive inhibition of androgen, DHT, and testosterone, binding to cancer cells and tissue is stopped and cancer stops growing
High (T3a or Grade 4 or 5 or) PSA > 20 or Very High (T3b-T4, Primary Gleason pattern 5, or >4 cores with Grade Group 4 or 5) expected survival being 5 years or less and asymptomatic:
initial therapy should be either (1, 2, or 3) 1. Observation or 2. ADT or 3. EBRT
Docetaxel for PC, clinical pearls
it is given with a steroid for CRPC because it can cause edema and the steroid is to mitigate that. It can also cause a hypersensitivity reaction. We pretreat with diphenhydramine (H1RA) or famotidine (H2RA) or may give a steroid on the day they get the drug to minimize the hypersensitivity reaction during infusion One of the main reasons it is discontinued is because of the peripheral neuropathy that can be intolerable
PSA for prostate cancer specificity
it is specific for the prostate, NOT cancer. Any manipulation of the prostate (ex. biopsy to the prostate, TURP, BPH, prostatitis) can all increase levels of PSA. PSA may be reduced in patients on 5alpha reductase inhibitors
What is the main role of the prostate
keep seminal fluid viable after being released
LH
luteinizing hormone
LHRH
luteinizing hormone releasing hormone
How does age play into Prostate Cancer risk
most frequently diagnosed among men aged 65-74. median age of diagnosis is 67 The graph showed an increase in % of new cases as age increased up until 74 years old and then it falls off afterwards. The drop in diagnosis after 74 is due to changes in screening practices in older men
Clinical presentation of localized Prostate cancer
most patients have localized disease. Most patients with localized disease are asymptomatic
CRPC 1st line Treatment Options Abiraterone (Zytiga, Yonsa) • MOA
selectively and irreversibly inhibits CYP17, an enzyme required for androgen biosynthesis which is expressed in testicular, adrenal, and prostatic tumor tissues. Inhibits formation of the testosterone precursors dehydroepiandrosterone (DHEA) and androstenedione this is basically an androgen biosynthesis inhibitor
Second-line Therapies for CRPC: Cabazitaxel (Jevtana) MOA:
taxane derivative which is a microtubule inhibitor; it binds to tubulin promoting assembly into microtubules and inhibiting disassembly which stabilizes mts. This inhibits microtubule depolymerization and cell division, arresting the cell cycle and inhibiting tumor proliferation. So once a patient has had treatment prior with docetaxel and progressed, you can consider this (or carboplatin or cisplatin) which is similar to docetaxel
CRPC 1st line Treatment Options Abiraterone (Zytiga, Yonsa) • Available in different tablet formulations:
the conventional formulation is Zytiga and a micronized [fine particle] formulation is Yonsa. Formulations are NOT interchangeable • Dosing for metastatic CRPC: - Zytiga: 1000mg PO QD in combo with prednisone 5mg PO BID - Yonsa (micronized formulation): 500 mg QD in combo with methylprednisolone 4 mg BID • Dosing for metastatic high-risk castration sensitive prostate cancer - Zytiga: 1g PO QD in combo w prednisone 5 mg QD -Take Zytiga orally on an empty stomach, at least 1 hour before and 2 hours after food. • Abiraterone micronized (Yonsa) may be administered without regard to food. Swallow tablets whole with water; do not crush or chew. • Available as Yonsa: 125 mg; Zytiga: 250 mg, 500 mg
Testosterone pathway
the hypothalamus send out LHRH and stimulates the release of LH and FSH from the pituitary gland. LH stimulates the production of testosterone and small amounts of estrogen FSH promotes maturation of LH receptors Testosterones has a big role in PC cell growth Circulating testosterone which is influenced by the release of LHRH, LH, and FSH, is done through a negative feedback loop at the hypothalamus and pituitary gland
Castration Sensitive Prostate Cancer: choice of regimen
• Choice of regimen involves discussion with patient about potential toxicities of abiraterone and docetaxel as well as cost of treatment Either [ADT + A] or [ADT + D] When patients are metastatic, that's when you consider adding other agents to ADT (vs ADT alone)
Screening for Prostate Cancer
• Controversial; different recommendations by several organizations • Balance of benefits of screening (preventing mortality for a highly indolent cancer) vs harm of over-diagnosis and overtreatment (complications from biopsy, urinary complications, ED, infections) • The decision to screen is determined by patient's life expectancy. (Social security/life insurance calculator).
Sipuleucel-T (Provenge) for CRPC
• Dendritic cell vaccine (autologous cellular therapy) designed to enhance immune T Cell (Immune) response against prostatic acid phosphatase (PAP) (PAP drives growth of cancer cells) • Prepared from peripheral blood mononuclear cells obtained by leukapheresis and gets exposed to novel recombinant protein immunogen (PAP fused to GM-CSF). Then, lab cultures it to have the product infused back into the patient 3 days post harvest. Then in the patient, it induces T cell immunity to tumor that expresses PAP which is found in PC cells. • Given at ~2 week intervals for 3 total doses • SEs: infusion reaction, chills, fever, fatigue, headache -Premediate with tylenol + antihistamine 30 mins before giving the agent
PSA (Prostate Specific Antigen)
• Glycoprotein produced by prostate epithelial cells • Specific for the prostate, not for cancer - Can be lowered by 5 alpha-reductase inhibitors (finasteride/dutasteride) - Can be increased in BPH
LHRH Counseling Points for treatment in PC
• Initial disease flare caused by initial induction of LH/FSH → Increased testosterone production - Presents clinically as increased bone pain (if metastatic) or increased urinary symptoms - Resolves after about 2 weeks! - Starting an antiandrogen before the administration of LHRH agonist and continuing for 2-4 weeks frequently used to mitigate tumor flare • Baseline bone mineral density test before starting long-term ADT since it can cause OP - Start on Calcium and Vitamin D supplement
LHRH Mechanism of Action in PC treatment
• Intermittent pulsed LHRH (aka GnRH), which mimics endogenous release, causes sustained released of LH and FSH • High dose/continuous administration of LHRH inhibits gonadotropin release caused by receptor downregulation • This downregulation of pituitary receptors causes an overall decrease in testosterone production
Combined Androgen Blockade for PC
• LHRH agonist + antiandrogen • Most patients respond to initial hormonal manipulation, but almost all relapse within 2-4 yrs after starting therapy d/t tumor cells that are hormone independent. Tumor is also stimulated by extratesticular androgens converted intracellularly to DHT • Associated with more adverse events • Controversial: can be used an initial therapy or add after several months if androgen ablation incomplete. The question is "should it be started initially or be added on several months post androgen blockade?"
Staging System for prostate cancer (tumor size and local extent of the primary tumor)
• Nomenclature: T,N,M = Tumor, Node, Metastasis • Tumor (T) - Clinical T staging is based on the results of the DRE, transrectal ultrasound (TRUS)-guided biopsy findings, and imaging studies - Pathologic T staging is possible for patients who undergo radical prostatectomy; provides more accurate assessment • Node (N) - Both clinical and pathologic staging define regional lymph nodes as not assessed (NX), negative (N0), or positive (N1) • Metastasis (M) - Patients are classified as either not having distant metastasis (M0) or distant metastasis present (M1)
Antiandrogens for PC
• Not monotherapy (used in combo w LHRH agonists) • Three first-generation agents - Bicalutamide (Casodex) 50mg QD - Flutamide 250mg (Eulexin) TID - Nilutamide (Nilandron) 300mg QD x 1 month, then 150mg/day
LHRH antagonist for PC treatment
• Only 1 FDA approved! Degarelix (Firmagon) • Must be given SQ monthly; loading dose 240mg x 1, then 80mg q 28 days thereafter • Pros: -Faster drop in testosterone levels (Castration levels seen in 7 days compared to 28 days w/ LHRH agonists) - No tumor flare and thus NO antiandrogen needed • Cons: less flexibility in dosing schedule, high cost
Factors to Consider for Initial Treatment of PC
• Patient's general medical condition • Recurrence risk • Expected survival • Surgery (radical prostatectomy or remove prostate) appropriate if tumor confined to prostate and life expectancy > 10 years; significant perioperative morbidity • Treatment based on risk stratification rather than stage. (risk is dependent on many things so put them in a risk/survival group to get initial therapy)
Prognostic Factors in prostate cancer (which affects management)
• Prostate Specific Antigen (PSA) • Tumor size • Local extent of the primary tumor • Histologic grade - Gleason Score
LHRH agonists in PC treatment
• Reversible method of androgen ablation • As effective as surgical orchiectomy • Goal serum testosterone <50ng/dL one month after starting therapy (castration level) • No direct comparative trials between agonist agents • Choice based on cost and patient/physician preference for dosing schedule. (but most people on this because they don't want their testes removed)
What do the values of the gleason score mean in PC
• Score ranges from 1 to 5 for each prominent pattern • Scores are added together (ex. 3 + 4); total score AKA Gleason score is between 2-10 -Lower Gleason scores (2-4) tend to be less aggressive -Higher Gleason scores (7-10) tend to be more aggressive
Supportive Care in PC
• Screening and intervention to prevent/treat diabetes and CV disease in pts on ADT -Patients with all modalities will usually end up on ADT which increases the risk of DM, CV disease and other long term issues we must monitor periodically. • ADT associated with 21-45% relative increase in fracture risk due to decrease in BMD - Baseline and yearly DEXA scans - Calcium 1200mg and vitamin D 800 IU supplements
What is the prostate?
• Solid, rounded, heart-shaped organ positioned between the neck of the bladder and the urogenital diaphragm • Produces the seminal fluid that nourishes and transports sperm • Composed of acinar secretory cells arranged in a radial shape surrounded by a foundation of supporting tissue • 95% of prostate cancer cases are caused by adenocarcinoma (major cell type or histology cell type)
Clinical presentation of Locally invasive disease in Prostate cancer
• Ureteral dysfunction • Urinary frequency • Urinary hesitancy • Dribbling
