Benign prostatic epithelium and prostatic carcinoma were biochemically analogous and respond in similar fashion in androgen ablation
Mechanism of androgen blockage?
Four therapeutic approaches for androgen axis blockade are in current clinical use:
- (1) ablation of androgen sources - subcapsular orchidectomy, Because the plasma half-life of testosterone is 10 to 20 minutes, patients who undergo bilateral orchiectomy are functionally castrate within 1 to 2 hours after surgery, within 24 hours, serum testosterone falls by 90% and reach the castration level
- (2) antiandrogens,
- (3) inhibition of LHRH and/or LH release, and
- (4) inhibition of androgen synthesis
The androgen receptor is not directly affected by ADT, leading many to hypothesize that hormone-refractory prostate cancer is a reactivation of androgen receptor–mediated pathways.
Androgen withdrawal may partially exert its effect on the prostate through vascular effects.
What is complete androgen blockage?
Androgen deprivation can be achieved by either suppressing the secretion of testicular androgens or inhibiting the action of circulating androgens at the level of their receptor. These two methods can be combined to achieve what has been known as complete (or maximal or total) androgen blockade (CAB).
Combined androgen blockade is designed to block the possible contribution of adrenal androgens to prostate cancer progression.
In studies of combined androgen blockade using the steroidal antiandrogen cyproterone acetate compared to LHRH agonists alone, the outcomes were slightly worse with the combination, suggesting increased non–prostate cancer deaths with this agent.
A clinical trial comparing surgical castration alone with surgical castration combined with flutamide did not show a significant benefit in men with minimal metastatic disease.
At a dose of 1 to 3 mg/day with no prophylactic breast irradiation, DES is the cheapest form of ADT. Increased cardiovascular toxicity
LHRH agonists would be cheaper than scrotal orchiectomy only if the patient lived a few months after the administration of ADT.
Combined androgen blockade is the most expensive form of ADT.
Estradiol is a 1000-fold more potent at suppressing LH and FSH secretion by the pituitary compared with testosterone. Treatment with oestrogens results in testosterone suppression and is not associated with bone loss. Due to severe side effects, especially thromboembolic complications, even at lower doses these drugs are not considered as standard first-line treatment.
Explain the newer modalities of hormone therapy in prostate cancer. (TU 69,10)
have androgen agonist activity
(mutation of the AR gene allowing the antiandrogen to behave as an activator of AR)
Non-steroidal or pure
- Steroidal -
- - block the effects of testosterone on the receptor as well as lower testosterone through their progestational central inhibition effect.
- - side effects are consistent with the hypogonadal state and include loss of libido, erectile dysfunction, and lassitude. Severe cardiovascular complications can occur in up to 10% of patients. Associated with hepatotoxicity, fluid retention and thromboembolism.
- - cyproterone acetate (CPA)
- - megestrol acetate
- - medroxyprogesterone acetate.
- Unlike the steroidal antiandrogens, which have central progestational inhibitory effects, the nonsteroidal antiandrogens simply block androgen receptors, including those in the hypothalamic pituitary axis. Because those central androgen receptors no longer sense the normal negative feedback exerted by testosterone, both
LH levels and—as the normal testicular response to increased LH —testosterone levels increase (1.5 times normal). This allows antiandrogen activity without inducing hypogonadism: potency therefore can be preserved. Peripheral conversion of this excessive testosterone also increases estrogen levels, leading to the gynecomastia and mastodynia associated with the nonsteroidal antiandrogens.
- - Flutamide - gastrointestinal toxicitymainly diarrhea
- - Bicalutamide - The dosage licensed for use in CAB is 50 mg/day, and 150 mg for monotherapy.
- - Nilutamide - Delayed adaptation to darkness , interstitial pneumonitis which can progress to pulmonary fibrosis [@ निलो दृश्य, pulmonary issue - hypoxia - cyanosis - निलो)
Liver toxicity with all non steroidal antiandrogens - LFT test should be done
Second generation anti-androgens?
They disrupt the translocation of the AR from the cytoplasm (where it is inert) into the nucleus (where it acts as a transcription factor). Don't have androgen agonist activity when AR is overexpressed. Much more strong AR antagonist, as compared with the first generation.
Enzalutamide - Enters brain [@ Enza Enters] , causes seizure, approved for metastatic disease
Apalutamide - does not enter the brain, no seizure, not approved for metastatic disease
Liver toxicity is a possible side effect all antiandrogens
What is Antiandrogen Withdrawal Phenomenon?
- Patients treated with a combination of an antiandrogen and an LHRH agonist can experience a decline in PSA and even in objective responses with the withdrawal of the antiandrogen from the combination.
- Based on this response, it appears that the antiandrogen is actually exerting agonistic activity on prostate cancer cells.
- This phenomenon has now been demonstrated with all antiandrogens, including cyproterone acetate, as well as with DES and progestational agents.
It has been postulated that mutations in the AR gene may underlie this phenomenon, allowing the antiandrogen to behave as an activator of the AR.
- Luteinising-hormone releasing hormone antagonists immediately bind to LHRH receptors, leading to a rapid decrease in LH, FSH and testosterone levels without any flare.
- The direct antagonistic activity eliminates the LH and testosterone flare, which is the major therapeutic advantage of these agents: there is no need for antiandrogen coadministration.
- The practical shortcoming of these compounds is the lack of a long-acting depot formulation with, so far, only monthly formulations being available.
- If the patient is high cardiac risk, urge strongly to start with antagonist, because agonists have high cardiac morbidity. Though, antagonists are to be given monthly and are expensive. If patient is affordable, always use antagonists, they are better drugs.
- In case of large volume mets, compressing the spinal cord or with large bulky prostate, then you should start with antagonists. (EAU) After 2-3 cycles, can be switched to agonists.
- Abarelix - allergic reaction
- Degarelix - no allergic reaction, 240 mg in the first month, followed by monthly injections of 80 mg. Most patients achieve a castrate level at day three.
- Relugolix - first and only oral GnRH receptor antagonist approved by FDA in 2020
[@ अब देगा रेल का सिट]
- Long-acting LHRH agonists are currently the main forms of ADT.
- These synthetic analogues of LHRH are delivered as depot injections on a 1-, 2-, 3-, 6-monthly, or yearly, basis.
- The first injection induces a transient rise in luteinising hormone (LH) and follicle-stimulating hormone (FSH) leading to the ‘testosterone surge’ or ‘flare-up’ phenomenon which starts two to three days after administration and lasts for about one week.
- This may lead to detrimental clinical effects (the clinical flare) such as increased bone pain, acute bladder outlet obstruction, obstructive renal failure, spinal cord compression, and cardiovascular death due to hypercoagulation status. Patients at risk are usually those with high-volume symptomatic bony disease. Concomitant therapy with an anti-androgen decreases the incidence of clinical flare but does not completely remove the risk.
- Anti-androgen therapy is usually continued for 4 weeks but neither the timing nor the duration of anti-androgen therapy are based on strong evidence.
- Chronic exposure to LHRH agonists results in the down-regulation of LHRH-receptors, suppressing LH and FSH secretion and therefore testosterone production. A castration level is usually obtained within 2 to 4 weeks.
- Coadministration of an antiandrogen for 21-28 days functionally blocks the increased levels of testosterone.
- LHRH agonsits include Leuprolide, Goserelin or Triptorelin
- All LHRH agonists are administered either IM or subcutaneously.
- Widespread use of orally effective LHRH agonists has been limited by severe allergic reactions in some patients, even after previously uneventful treatment.
The dose of leuprolide?
For endometriosis, breast cancer - 3.75mg 3 monthly
- For CaP
- - 22.5mg 3 monthly (im/sc) ?
- - Coadministration of bicalutamide 150mg OD for 21-28 days
- - Administration of Calcium 1500mg/day and Vitamin D 400IU/day
It is highly viscous. Use one syringe to dissolve it, and another fresh syringe to give the medicine. Make sure the medicine does not freeze in the syringe and the medicine is spilled
Inhibitors of androgen synthesis?
- - inhibit the conversion of cholesterol to pregnenolone
- - inhibit 17 alpha-hydroxylase and 17,20 - lyase
- - coadminister cortisol
- - 4 hours castrate level reached, at around 4 months- testosterone level reaches to normal
- - side effects - gynecomastia, lethargy, weakness, hepatic dysfunction, visual disturbances
- - Selective inhibitor of cytochrome p450 isoform 17 (CYP17), an enzyme that has 17 alpha-hydroxylase and 17,20-lyase activity
- - deplete adrenal and intratumoral androgens
- - most serious side effect is hepatotoxicity, LFT every 2 weeks
- - increase in mineralocorticoids, deoxycorticosterone and corticosterone result in hypokalemia, hypertension and fluid overload. Coadministration of prednisolone suppresses the increase in ACTH resulting from decreases in cortisol and mineralocorticoid excess.
- - coadminister cortisol
Complications of androgen ablation?
[@ HAS DOC MG - Hot flashes, Anemia, Sexual, Diabetes, Obesity, Cardiovascular, Muscles, Gynecomastia - हास् डाक्टर MG]
- Hot flashes - SSRI Venlafexine 12.5mg BD
- Sexual dysfunction/Erectile dysfunction - PD5I
- Cognitive function
- Changes in body habitus - loss of muscle, increase in fat
- Diabetes and Metabolic syndromes
- Cardiovascular morbidity and mortality
- Gyencomastia - Prophylactic radiation therapy (10 Gy) has been used to prevent or reduce gynecomastia and mastodynia, but it has no benefit once these side effects have already occurred. Once they are present, a simple mastectomy may be required in some men for cosmetic and symptomatic relief.
Monitoring and management of bone problems in patient with ADT?
BMD of the hip as measured by dual-energy x-ray absorptiometry should be considered for all men who are anticipated to be on long-term ADT.
- Dual-energy X-ray absorptiometry (DEXA) -
- - Normal is a T-score of −1.0 or higher
- - Osteopenia is defined as between −1.0 and −2.5
- - Osteoporosis is defined as −2.5 or lower, meaning a bone density that is two and a half standard deviations below the mean of a 30-year-old man/woman.
- The longer a man remains on ADT, the greater the risk of fracture. It has been estimated that 4 years of ADT will place the average man in the osteopenia range.
- Offer men starting on long-term ADT dual emission X-ray absorptiometry (DEXA) scanning to assess bone mineral density (Strong, EAU 2021)
- If no bone protective agents are given, a DEXA scan should be done regularly, at least every 2 years. Vitamin D and calcium levels should be regularly monitored when patients receive ADT and patients should be supplemented if needed.
- Treatment of osteoporosis
- - Smoking cessation
- - Weight-bearing exercise
- - Calcium - 1200 to 1500 mg/day
- - Vitamin D - 400 IU/day
- - Indication of use of bone protective agents
- 1. Presence of osteoporosis
- 2. with an additional risk factor for osteoporosis
- 3. annual bone loss confirmed to exceed 5%
- 4. severe fracture.
Bisphosphonate therapy - zoledronic acid IV, oral alendronate
Shelcal-500 Tablet contains Calcium 500mg and Vitamin D3 250 IU as active ingredients.
Short note on Zoledronic acid?
Reduce bone resorption by inhibiting osteoclastic activity and proliferation.
4 mg diluted in 100 ml given as a single IV in no less than 15 minutes, repeated at 4 weeks interval for several months. It requires renal dose adjustment.
- Side effects
- - hypocalcemia, use concomitant administration of calcium and vitamin D
- - Osteonecrosis of jaw (ONJ) - always do dental consultation before starting zoledronic acid
- - Contraindicated in renal failure
MOA of Denosumab?
Receptor activator of Nuclear factor KB Ligant
- It is human monoclonal antibody that binds RANKL, preventing RANKL from activating RANK, its receptor on the osteoclast surface.
- With reduced RANK–RANKL binding, osteoclast formation, function and survival are inhibited, bone resorption decreases and bone mass
- S/E - ONJ, supplement ca and vitamin D
- Dose - 120mg sc every 4 weeks
Is biopsy always required before hormonal therapy/castration?
Guidelines say yes
If PSA > 100, patient extremely moribund, spinal compression - can go directly for castration without biopsy
Immediate versus delayed ADT?
- Immediate ADT
- - Immediate ADT in LAPC/asymptomatic metastasis, ADT results in significantly better prostate cancer-specific survival but, not better overall survival
- Delayed ADT
- - ADT started only when disease progress (increased pain, mets in location that may produce serious complications, decreased performance status, ureteric obstruction)
In symptomatic patients immediate treatment is mandatory, however, controversy still exists for asymptomatic metastatic patients due to the lack of high quality studies.
Continuous Vs Intermittent ADT?
Another approach to minimizing AD-related morbidity is the intermittent application of androgen suppression.
If PSA 4 - stop ADT
If PSA > 10/20 or baseline (different studies) - Restart ADT
The duration of intermittent ADT progressively shortened over time: the median interval of the “off cycle” was 20.1 months for the first interval, 13.2 months for the second cycle, 9.1 months for the third, and 4 to 5 months thereafter.
- Disease-specific death (prostate cancer and related treatments) was more common in the intermittent-therapy arm compared to the continuous-therapy.
- Intermittent ADT compared with continuous therapy is not superior and may be worse.
Hormonal therapy in Carcinoma Prostate -EAU 2020
In Radical Prostatectomy - not useful in the neoadjuvant setting
- In Radiotherapy (Hormonal therapy should not be given alone)
- Low risk - no benefit
- Intermediate risk - short-term neoadjuvant (2 months before) plus concomitant ADT (4 to 6 months)
- High risk - long-term ADT (2 to 3 years)
- Locally advanced - long-term ADT (2 to 3 years)
Before hormonal therapy, always do the cardiac evaluation.
Note - In hormonally intact men with symptomatic metastatic prostate cancer, ADT is always indicated.
The longer application (longer than 6 to 9 months) of AD in conjunction with radiation therapy may be associated with increased rectal morbidity as well as sexual dysfunction.
Patients with LAPC (no evidence of metastasis, PSA upto 40) who had received external-beam radiotherapy plus 6 months of androgen suppression to two groups, one to receive no further treatment (short-term suppression) and the other to receive 2.5 years of further treatment with a luteinizing hormone–releasing hormone agonist (long-term suppression).
LHRH analogue (goserelin), initiated on the first day of irradiation (70Gy), and an antiandrogen agent (750 mg of flutamide per day or 50 mg of bicalutamide per day), initiated 1 week before the start of treatment with the LHRH analogue. Triptorelin was used
Results - combination of radiotherapy plus 6 months of androgen suppression provides inferior survival as compared with radiotherapy plus 3 years of androgen suppression in the treatment of locally advanced prostate cancer.
ADT-induced radiosensitizing effect of the tumour cells resulting in a significantly improved local tumour control.
If urinary symptoms
Aggressive TURP - high rate of incontinence in 20-40% of patients