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116 Cards in this Set

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Describe environmental etiological data regarding prostate cancer
Highest incidence is in Western Europe and US. Unknown factor. Lowest incidence is in Asia.
Describe the Genetic etiological data regarding prostate cancer
Patients with family history are at higher risk, African americans are more likely to develop versus caucasians.
Describe the role of diet in the developement of prostate cancer.
High fat diets have been implicated since fats are precursors to androgens which predispose patients to cancer.
Describe the hormonal factors involved with Prostate Cancer
Prostate cancer is dependent on androgen.
Describe where androgens are produced
95% in the testes and 5% in the adrenals
What is the principal androgen?
Testosterone
Describe hormonal pathogenesis for prostate cancer.
Testosterone is taken up by prostate cancer cells, then activated to dihydrotestosterone by 5-a reducatase enzyme. D combines with cytoplasmic receptor R and the complex enters the nucleus where it stimulates prostate cell growth.
Normal testosterone functions.
Maintaining sexual drive, inducing secondary sex characteristics.
Describe Dihydrotestosterone actions.
Responsible for prostate growth.
Is there a cure for metastatic prostate cancer?
No
Describe the local route of spread for the tumor.
Seminal vesicles, bladderr, periprostatic tissue.
Describe which lymph systems can be invaded by Tumors
Pelvic, abdominal or distant.
Describe vascular involvement in terms of prostate cancer
Bones of axial skeleton, viscera (lungs, liver, adrenals)
Describe Symptoms of Local disease
Urinary voiding symptoms
Describe symptoms of metastatic disease
Bone pain, anemia/fatigue, weight loss, dyspnea, lymphedema, lymphadenopathy, uteral obstruction, acute renal failure, CNS effects, gross hematuria, rectal bleeding
Stage A, Local or Metastatic? Curable?
Local, Curable
Stage B, Local or Metastatic? Curable?
Local, Curable
Stage C, Local or Metastatic? Curable?
Locally metastatic, may/may not be curable
Stage D, Local or Metastatic? Curable?
Widely metastatic, not curable
Describe PSA
Prostate specific antigen is a glycoprotein that normally liquifies semen after ejcaulation. It is secreted by the glandular epithelial cells of the prostate.
Normal non-age-specific PSA total serum level
0-4ng/ml
Why is PSA useful in tracking prostate cancer?
Prostate cancer disrupts the normal prostate architexture, thus PSA which normally is confined diffuses into the prostatic stroma and escapes into the vasculature.
3 Main uses of PSA
Diagnosis (not alone, with dre)
Staging
Monitoring Tx Response
Can PSA by itself be used for diagnosis?
No, too many false positives, must be used with DRE
Do PSA levels directly correlate with tumor size/progression?
No
Male patient's over the age of ________ with a life expectancy of at least 10 years should have an annual DRE and PSA checkup.
50 years
High risk patients such as _____(a)_______ or _____(b)____ should begin DRE/PSA testing annually at ___________
a: African americans
b: those with family history
c: earlier age (40yo)
3 Strategies to improve the usefulness of PSA as a tumor marker
1. Age specific normal value ranges
2. Free PSA
3. Prostate Velocity
Describe the following PSA strategy, "Age-specific normal value ranges"
Since the prostate normally enlarges as people age it is capable of producing more PSA, therefore the ranges need to adjust based on age.
Describe the following PSA strategy, "Free PSA"
Two forms of PSA circulate in the vasculature, free and complexed. The free concentration is inversely related tot he probability that the patient has cancer. Thus, if free PSA is less than 25% of total PSA, then there is a high probability of cancer (especially if total PSA is 4-10ng/ml)
Describe the following PSA strategy, "Prostate Velocity"
This method assesses the rate at which PSA increases from year to year. An increase of 0.75ng/ml/year warrants further investigation.
Describe the implications of Finasteride/Proscar on PSA tests and what is done about it?
5-Alpha reductase inhibitors such as finasteride produce a 50% reduction in PSA after 6-12 mo of treatment, thus, you must get a pre-finasteride PSA level as baseline.
How do you assess a PSA level in a finasteride patient?
Double measured level first.
What affect can a DRE have on PSA levels?
Physical manipulation of the prostate can cause levels to go up. PSA has a half life of 2-3 days. Therefore wait 10-15 days before drawing levels.
Describe Surgery for Conventional endrocrine therapy for metastatic prostate cancer
Bilateral Orchiectomy
Effect of Bilateral orchiectomy on Pituitary LH secretion
Increase
Effect of bilateral orchiectomoy on Testicular Androgen production
decrease
Indications of Endocrine therapy and outcomes
To palliate symptoms of metastatic disease, does not prolong lifespan and does not CURE
Mechanism of Endocrine therapy
Reduce androgen stimulation of prostate cells
3 main methods of endocrine therapy.
Surgery (Bilateral orchiectomy)
Diethylstilbesterol
LHRH Superagonists
Two medical endocrine therapy approaches to metastatic prostate cancer
Diethylstilbesterol, LHRH superagonists
Diethylstilbesterol - why isn't it used any more?
LHRH agonists are safer
Diethylstilbesterol - Effect on pituitary LH secretion
Decrease
Diethylstilbesterol - Effect on testicular androgen production
Decrease
Leuprolide, goserelin, triptorelin, histrelin are examples of what?
LHRH Superagonists
Reason Diethylstilbesterol is not as safe as LHRH Superagonists
DES can worsen HTN or precipitate VTEs in this older population
Characteristics of Endocrine therapy for metastatic prostate cancer
1. Selective Ablation of gonadal (not adrenal) androgens.
2. Decreased serum T levels result in decreased libido and hot flashes
3. Usually started after Sx of metastatic disease develop
4. Usually continued as long as patient responds to it
5. Typically monotherapy
Indications for Endocrine therapy for metastatic prostate cancer
Palliative for symptoms of Stage D prostate cancer
Why is Bilateral Orchiectomy the preferred Endocrine Therapy for Metastatic Prostate cancer?
1. Can be performed with low Morbidity.
2. Produces less of an immediate release of T
3. Less expensive than Rx
4. One time procedure (convenient)
SOME PATIENTS WILL REFUSE SINCE THEY THINK IT IS MUTILATION (FINE... ENJOY THE PRICETAG AND PISSIN DROPS)
What does Bilateral orchiectomy do as far as hormones?
Reduces testosterone serum levels to that of someone who has had their balls cut off.
Mechanism of Leuprolide and the RELINs
After chronic use, GNRH superagonists desensitize/downregulate pituitary LH receptors. Decreases release of LH and thus testicular androgen production tanks.
Compare the efficacy of the various LHRH Superagonists
Same
Lupron GEN
Leuprolide IM
Eligard GEN
Leuprolide SQ
Viadur GEN
Leuprolide implant SQ
Zoladex GEN
Goserelin SQ
Trelstar Depot
Triptorelin IM
Vantas GEN
Histrelin SQ Implant
3 Brand names of Leuprolide
Lupron DEPOT, Eligard, Viadur
Brand name of Goserelin
Zoladex
Brand name of Triptorelin
Trelstar Depot
Brand name of Histrelin
Vantas
LHRH Superagonist ADR's
1. Hot flashes -menopause like state... Most do not require Tx, but you can use DES, Clonidine or Medroxyprogesterone
2. Gynecomastia - Surgery or radiation to reduce
3. Tumor/Dz flare - Initial surge of testosterone may cause symptoms of cancer to worsen. Clnically significant flares relatively uncommon.
4. Acute-on-chronic phenomenon
5. ED
6. Osteopenia
7. Pain at injection site
8. Anemia
Describe Tumor flare associated with LHRH Superagonists
Inital surge of T causes worsening of cancer symptoms.
High risk patients for clinically significant flares include those with impending spinal cord compression or impending ureteral obstructions.
Symptoms of Tumor/dz Flare
Worsening bone pain, difficulty walking, bladder or stool incontinence, acute renal failure
How do you avoid Tumor Flare associated with LHRH superagonists?
Avoid GNRH superagonists in high risk patients. If you need to use GNRH SA's, begin antiandrogen or a drug that will suppress effects of excessive LH release. Start approximately 1 week before first dose and continue for first 30 days.
What agents can be used to suppress LH surge after giving GNRH superagonist?
Ketoconazole, DES, Flutamide or Nilutamide
What is Acute-on-chronic phenomenon?
Essentially a flare reaction that occurs in patients receiving multiple GNRH SA doses. With each dose they experience a flare. Typically thought to be due to weaning off drug before next dose... may be due to lack of compliance.
Describe ED symptoms experienced by patients taking LHRH superagonists
Decreased serum T causes decreased Sex drive and secondary ED. ED will respond to PDEi's
How do you prevent osteopenia associated with LHRH SA use and why does it occur?
Due to long use of LHRH SA's, to prevent give calciuma nd vitamin D supplements, weight bearing exercise and a biphosphonate.
Describe affect of LHRH SA's on hemoglobin
10% reduction, leads to anemia, also worsened if bone marrow is invaded.
Describe the 2 types of antiandrogens
Steroidal and non-steroidal
Describe the MOA of Steroidal Antiandrogens
Dual MOA:
1. Decrease androgen production
2. Block androgen at its cellular receptor in the cancer cell.
Describe the ADR's associated with decreased androgen production from Steroidal Antiandrogens
Decreased libido and ED
Examples of Steroidal Antiandrogens
Progesterone, Medroxyprogesterone
Describe the MOA of Nonsteroidal Antiandrogens
These agents are pure anti-androgens and block androgen at its cellular receptors.
Do nonsteroidal Antiandrogens have an effect on serum testosterone levels?
No
Implications of serum testerone level preservation using nonsteroidal antiandrogens
Males do not loose sexual function, preferred in younger sexually active males.
Which nonsteroidal antiandrogen is most convenient and is the safest?
Bicalutamide/Casodex
What ADR advantages exist with the use of Casodex?
Lower hepatotoxicity and diarrhea
Eulexin GEN
Flutamide
Nilandtron GEN
Nilutamide
Anandron GEN
Nilutamide
Casodex GEN
Bicalutamide
Flutamide BRAND
Eulexin
Nilutamide BRAND(s)
Nilandron, Anandron
Flutamide/Eulexin ADR
Diarrhea, GI upset, hepatotoxicity, gynecomastia, increased testosterone levels
Nilutamide/Nilandron or Anandron ADR
Difficulty with visual adaptation to darkness, pneumonitis, heaptoxicity, gynecomastia, alcohol intolerance
Bicalutamide/Casodex ADR
Diarrhea (less than flutamide), GI upset, hepatotoxicity, gynecomastia
Common ADR's among the Nonsteroidal Antiestrogens
Diarrhea, hepatotoxicity, gynecomastia
Specific indications for the use of Nonsteroidal antiandrogens
Stage D prostate cancer when combined with GNRH SA's or castration.
What is Maximal androgen ablation (MAB)?
Use of a GNRH SA, or Surgical castration plus nonsteroidal antiestrogen
Although improving the sexual lives of young stage D males, why is monotherapy with nonsteroidal antiandrogens not preferred?
Meta-analysis indicates that antiandrogen monotherapy is less effective than GnRH superagonist monotherapy.
Besides stage D, what other uses does MAB have?
Used in Stage B or C as an adjuvant to radiation treatment. This increases the response rate and prolongs life expectancy as compared to radiation alone.
Describe mechanism of gynecomastia associated with Nonsteroidal antiandrogens?
Unused Testosterone is converted to estrogen which stimulates breast development. 40-50% prevalence.
Which nonsteroidal antiandrogen is associated with the worst diarrhea?
Flutamide
Discuss the relative incidence of hepatotoxicity among the nonsteroidal antiandrogens
Flutamide and nilutamide are the biggest culprits. Bicalutamide is the BEST!
How would hepatotoxicity associated with nonsteroidal antiandrogen present and how would it be monitored?
Presents as increase in LFTs/jaundice, usually within 4-6 weeks. Monitor monthly for 4 months during initial Tx period then periodically thereafter.
INSTRUCT PATIENTS TO SEEK CARE IF THEY EXPERIENCE PERSISTENT NAUSEA, VOMITING AND ABDOMINAL PAIN!
Interstitial pneumonitis is reported with predominantly which nonsteroidal antiandrogen?
Nilutamide
Nuh! = Pneu!
Alcohol intolerance is reported with predominantly which nonsteroidal antiandrogen?
Nilutamide
Which nonsteroidal antiandrogen is delayed adaptation to the dark reported predominantly with?
Nilutamide
Which nonsteroidal antiandrogen pretty much sucks as far as ADRs?
Nilutamide
Which nonsteroidal antiandrogen agent has reports of increased serum testosterone?
Flutamide
When should hormonal therapy be initiated for a stage D patient?
At diagnosis, not when symptoms develop
Based on the studies performed by the VA, when should hormonal therapy be initiated on a stage D patient?
When symptoms of metastatic disease present. However, we recommend starting early because reviews of the study indicates that younger patients with high grade tumors have improved survival and also studies indicate that tumors respond to chemotherapy when they are smaller in size. So HA! VA, go back and play with your vietnam nutcases.
Describe the rationale behind using initial combination therapy
Gonadal ablation will only elminate DHT levels by 60%, therefore adrenal androgens can still feed the cancer. Therefore, combination therapy which elminates both adrenal and testicular androgen effects may produce a better response and decrease the likelihood of relapse.
Other names of Maximal Androgen Blockade
CAB: Combinational androgen blockade
TAB: Total androgen blockade
Examples of MAB
Orchiectomy + Antiandrogen OR
GnRH superagonist + Antiandrogen
Describe some benefits of MAB therapy
1.Reduce likelihood of GNRH SA flare
2.Prolongs survival for those with low volume metastatic disease on bone scan with a good performance status.
3.Prolongs progression free period by 3-7 months for patients who survive 5 years and continue to take combination therapy
What are disadvantages of MAB therapy (combination therapy)
1.Expense
2.More ADR (Diarrhea)
3.Life prolongation is modest
3 main strategies to improve response to hormonal therapy for stage D cancer
1.Initiate @ Diagnosis
2.Combination Therapy (MAB)
3.Withdraw Antiandrogen from combination therapy
Describe the rationale behind removing the antiandrogen agent in the course of combination hormone therapy for stage D patients
Typically results in a decrease in PSA, an improvement in clinical Sx and occasional radiographic improvement when the antiandrogen is stopped.
What is the mechanism by which discontinuation of continuous AntiAndrogen therapy is a beneficial strategy in the hormonal treatment of a stage D prostate cancer patient?
When used continuously, antiandrogens may mutate the receptor so instead of inhibiting growth of the tumor, the antiandrogen can stimulate growth of androgen-independent cells which can cause a relapse or progress the disease. By stopping the Antiandrogen you are giving the androgen-dependent cells a chance to grow that are more slow growing and less invasive.
Major advantage ADR wise of Antiandrogen withdrawal syndrome.
No ADR's associated with withdrawal.
Describe the mechanism by which 5-a reductase inhibitors can help prevent prostate cancer.
These agents block the conversion of testosterone to DHT inside prostate cancer cells. Since prostate cancer requires androgens to proliferate, these agents may prevent the production of one of the co-carcinogens responsible for the development of the tumor.
Are 5-a reductase inhibitors currently recommended for prostate cancer prophylaxis and why?
No.
1. When there was cancer, it was high grade
2. There is no proof that it affects life survival.