Androgen Treatment For Prostate Cancer

Types Of Hormone Therapy

Hormone therapy for prostate cancer can be done with medicines or surgery.

Medicines that may be used include:

LHRH agonists.

These medicines stop the testicles from making testosterone. At first they may cause a brief testosterone increase that can sometimes cause problems.

LHRH antagonists.

These medicines also stop the body from making testosterone. But they avoid the testosterone flare caused by LHRH agonists.

Androgen synthesis inhibitors.

These medicines block enzymes that the body needs to make testosterone. So they can lower testosterone levels more than other treatments.

Antiandrogens.

These medicines block the adrenal glands from making testosterone. An antiandrogen may be used along with an LHRH agonist or antiagonist. This is called combined androgen blockade.

Surgery to remove the testicles is another way to reduce testosterone. The testicles make most of the body’s testosterone. Removing them lowers testosterone levels immediately.

Surgery is the simplest and quickest way to reduce androgen levels. But the effects are permanent.

Lowering Adrenal Gland Androgen Levels

Because LHRH agonists and antagonists only lower testosterone production levels in the testicles, other treatments may be needed to lower androgens made by the adrenal glands or the prostate cancer itself.

Medications that lower adrenal gland androgen levels include:

• Zytiga® : Taken orally each day, this treatment is often used when cancer has spread to the bones or if the patient is high-risk or has castrate-resistant prostate cancer, meaning its still growing despite low testosterone levels.
• Nizoral® : This treatment is also taken orally and works similarly to abiraterone. Its also used in men with advanced prostate cancer whose cancer has spread.

Other Evidence To Support Lower Testosterone Levels And Improved Outcomes

The historic investigations known as the Veterans Administration Cooperative Urological Research Group studies formed a basis for the treatment of prostate cancer with DES before the availability of LHRH analogues. Due to higher death rates in the 5-mg DES treatment arm in VACURG I, lower DES doses were studied in VACURG II. Patients were randomized to 3 different dose ranges of DES versus placebo.43 Men receiving 0.2 mg/day of DES had a significantly shorter overall survival than men receiving 5 mg/day. VACURG II showed some survival benefit for hormonal treatment when Kent and associates44 reported that 0.2 mg/day and 1 mg/day of DES failed to consistently suppress testosterone to castrate levels. These data suggest that ineffective androgen suppression may reduce survival in advanced prostate cancer.

Several studies have demonstrated that the addition of an antiandrogen to orchiectomy did not improve overall survival, whereas the addition of an antiandrogen to an LHRH analogue did.4547 Although specific testosterone data are not available, it does suggest that ineffective or inconsistent testosterone suppression by LHRH analogues might be an explanation.

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Hormone Treatment Fights Prostate Cancer

Hormone therapy for prostate cancer has come a long way in the past few decades. Not so long ago, the only hormonal treatment for this disease was drastic: an orchiectomy, the surgical removal of the testicles.

Now we have a number of medications — available as pills, injections, and implants — that can give men the benefits of decreasing male hormone levels without irreversible surgery.

“I think hormonal therapy has done wonders for men with prostate cancer,” Stuart Holden, MD, Medical Director of the Prostate Cancer Foundation.

Hormone therapy for prostate cancer does have limitations. Right now, it’s usually used only in men whose cancer has recurred or spread elsewhere in the body.

But even in cases where removing or killing the cancer isn’t possible, hormone therapy can help slow down cancer growth. Though it isn’t a cure, hormone therapy for prostate cancer can help men with prostate cancer feel better and add years to their lives.

On average, hormone therapy can stop the advance of cancer for two to three years. However, it varies from case to case. Some men do well on hormone therapy for much longer.

Recommendation For Routine Testosterone Testing

T levels should be measured regularly in men receiving ADT to ensure T suppression is being maintained to target this does not appear to be the case in routine clinical practice. EAU guidelines recommend that T testing is performed 3 months after the first dose of ADT and repeated every 36 months thereafter. ADT use is often assumed to be a proxy for adequate T suppression to castrate levels however, neglecting to assess T will fail to identify levels above target, microsurges, and escapes. Adding a T test to the regular PSA assessment is simple to implement and would address these concerns.

With a rise in PSA and progression to CRPC, T testing and management remain important. Confirmation that T is castrate at time of CRPC diagnosis is critical, and continuance of regular testing should confirm effective T suppression and prevention of repopulation of partially androgen-sensitive tumor cells. An incorrect diagnosis of CRPC may prompt the use of additional, more costly, and possibly more toxic therapies in patients who do not yet require them .

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Laboratory Evaluations In The Management Of Prostate Cancer

PCa is an almost unique therapeutic area in that regulatory approvals of drugs such as LHRH agonists and antagonists are based on achievement of endpoints for a defined biochemical surrogate as opposed to clinical outcomes. A similar example would be the approval of statins based on reductions in LDL cholesterol before CV clinical endpoints had been achieved. This concept supports the use of laboratory measurements during PCa treatment as being appropriate to assess response to therapy, tumor microenvironment, state of disease progression and prognosis. Serum PSA levels are routinely evaluated as a biomarker of PCa diagnosis and progression . However, T may also be associated with clinical significance, including nadir levels, microsurges, and escapes during ADT additionally, measurement of FSH may also be relevant .

Hormone Therapy For Prostate Cancer

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• Current issues in hormone therapy

Hormone therapy is also called androgen suppression therapy. The goal of this treatment is to reduce levels of male hormones, called androgens, in the body, or to stop them from fueling prostate cancer cell growth.

Androgens stimulate prostate cancer cells to grow. The main androgens in the body are testosterone and dihydrotestosterone . Most androgens are made by the testicles, but the adrenal glands as well as the prostate cancer cells themselves, can also make androgens.

Lowering androgen levels or stopping them from getting into prostate cancer cells often makes prostate cancers shrink or grow more slowly for a time. But hormone therapy alone does not cure prostate cancer.

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Changes In Gleason Criteria

Two of the Gleason criteria are altered by NADT. A decrease in gland size and an increase in stroma between glands occur. These findings can lead to a false upgrade of the Gleason score. The use of a modified Gleason system has been proposed to evaluate prostatectomy specimens from patients who have received NADT some physicians have suggested that no Gleason score should be allocated.

How Does Hormone Therapy Work Against Prostate Cancer

Early in their development, prostate cancers need androgens to grow. Hormone therapies, which are treatments that decrease androgen levels or block androgen action, can inhibit the growth of such prostate cancers, which are therefore called castration sensitive, androgen dependent, or androgen sensitive.

Most prostate cancers eventually stop responding to hormone therapy and become castration resistant. That is, they continue to grow even when androgen levels in the body are extremely low or undetectable. In the past, these tumors were also called hormone resistant, androgen independent, or hormone refractory however, these terms are rarely used now because the tumors are not truly independent of androgens for their growth. In fact, some newer hormone therapies have become available that can be used to treat tumors that have become castration resistant.

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How Will I Know That My Hormone Therapy Is Working

Doctors cannot predict how long hormone therapy will be effective in suppressing the growth of any individual mans prostate cancer. Therefore, men who take hormone therapy for more than a few months are regularly tested to determine the level of PSA in their blood. An increase in PSA level may indicate that a mans cancer has started growing again. A PSA level that continues to increase while hormone therapy is successfully keeping androgen levels extremely low is an indicator that a mans prostate cancer has become resistant to the hormone therapy that is currently being used.

Androgenic Suppression Of Advanced Prostate Cancer Cells In Vitro

The delay of progression toward androgen-independency in IAD treatment might be related to the suppressive effect of androgen on AR-positive hormone-refractory prostate cancer cells that is observed in the LNCaP and other prostate cancer cell models. LNCaP is one of the most commonly used cell lines for prostate cancer research and was derived from a human lymph node metastatic lesion of prostate adenocarcinoma . LNCaP cells express AR and PSA. To establish relapsed androgen-ablation resistant prostate cancer cells that mimic the clinical situation in which prostate cancer recurs during androgen deprivation, we cultured androgen-sensitive LNCaP 104-S cells in androgen-depleted conditions in vitro. After 20 passages in androgen-depleted media supplemented with dextran-coated charcoal-stripped fetal bovine serum, most LNCaP 104-S cells undergo cell cycle arrest. After 60-80 passages , cells called 104-R1 cells emerge that grow much more rapidly in the absence of androgen. After 120-150 passages in androgen-depleted medium, 104-R1 cells give rise to cells called 104-R2 cells, that proliferate in the absence of androgen at a rate comparable to the proliferation rate of 104-S cells grown in media with androgen .

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Evolving View Of Suppression Targets For Testosterone

Historically, the definition of castration has been suppression of T to a level lower than 50ng/dL, based on radioimmunoassays developed in the 1960s that were less accurate when measuring lower levels of T. Advances in assay technology with greater sensitivities confirm that T levels following bilateral orchiectomy are approximately 15ng/dL .

A much less common form of PCa is small cell carcinoma that is highly malignant, presents with low PSA levels and has little dependency on AR signaling patients with this tumor do not usually benefit from ADT . Neuroendocrine differentiation can also occur in PCa that may lead to castration resistance before any rise in PSA .

There is increasing evidence that very low nadir T levels, particularly during the first few months of ADT, and absence of microsurges and escapes in T may be associated with improved clinical outcomes, including survival . This confirms the critical role of T in stimulation of PCa cells and emphasizes the importance of selecting an ADT with the greatest impact on T levels. During therapy, T should be monitored frequently to confirm achievement of targets, ideally to < 20ng/dL if not, consideration should be given to improving patient compliance or selecting an alternative ADT.

Hormone Therapy In Hormone

Hormone-sensitive cancer depends on hormones to grow. For those with early-stage prostate cancer thats at increased risk of spreading, hormone therapy may be given before, during or after radiation therapy or after surgery. It may also be used in men who have localized cancer and are unable to have other treatments.

For cancers that have recurred after radiation therapy or surgery, hormone therapy is the primary treatment. In patients with advanced prostate cancer, hormone therapy is usually combined with ADT and sometimes chemotherapy.

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Advantages And Disadvantages Of Nadt

Neoadjuvant androgen deprivation offers the following potential advantages:

• Rate of positive margins is reduced
• Organ-confined disease is increased
• Serum PSA level is reduced
• Prostate size is reduced.

The following disadvantages of NADT have been identified:

• Clinical trials have not demonstrated unequivocal improvement in disease-free survival rates
• NADT has an unknown therapeutic effect on microscopic local or metastatic disease
• Poorly differentiated areas of tumor are altered minimally
• Tumor is rarely completely eradicated
• Risk of androgen-independent clonal proliferation exists with prolonged NADT
• Ability to evaluate the extent of the tumor at surgical resection may be compromised
• Pathologic interpretation may be obscured
• Increased difficulty occurs at surgery due to periprostatic fibrosis
• Cost of therapy is a disadvantage
• Adverse effects are a potential disadvantage
• Treatment of the tumor is delayed
• Likelihood of requiring blood transfusion during surgery is increased

Testosterone Surges Escapes And Microsurges

Following the first injection of LHRH agonists, a surge in T due to hyperstimulation of the GNRH receptor will occur, followed by downregulation and subsequent inhibition of production of T by the testes. Escapes in T are possible where T levels rise before a subsequent dose. Morote et al. found that T levels above 32ng/dL resulted in a mean PFS of 88 months compared to 137 months for patients who did not experience escapes . Studies have also shown improved survival free of androgen-independent progression when T escapes are minimized .

Microsurges in T may occur following a subsequent dose if suppression of the hypothalamuspituitarygonadal axis has not been effectively maintained in some cases, this can be due to a delay in administration of the next injection . The definition of a microsurge is not standardized it is sometimes defined as an absolute increase in T of 25ng/dL . Additionally, the clinical implications of microsurges remain to be identified .

While the clinical significance of surges in T with the first dose of an LHRH agonist is unknown for most patients , it may be desirable to avoid the consequences of this initial rise and this can be achieved by coadministration of an antiandrogen, or initiation of ADT with an LHRH antagonist.

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Role Of Androgens In Prostate Cancer

Prostate cancer disease progression is initiated by the formation of prostatic intraepithelial neoplasia , which can progress to high grade PIN , followed by adenocarcinoma and metastasis. The prostate is heavily reliant on androgen for growth and function, and treatments targeting production of androgen or the AR itself are used in every stage of prostate cancer disease progression. Metastatic prostate cancer is the lethal phenotype of the disease and is typically treated with chronic androgen deprivation, usually by pharmacological means. Castration induces involution of the prostate and decreases the size of prostatic carcinoma , which forms the rationale behind androgen deprivation as a therapy. In rodent models, castration induced rapid apoptosis in the rat ventral prostate . Androgen deprivation also induces cellular senescence, a stable cell cycle arrest in response to sub-lethal stress.

How Is Hormone Therapy Used To Treat Hormone

Hormone therapy may be used in several ways to treat hormone-sensitive prostate cancer, including:

Early-stage prostate cancer with an intermediate or high risk of recurrence. Men with early-stage prostate cancer that has an intermediate or high risk of recurrence often receive hormone therapy before, during, and/or after radiation therapy, or after prostatectomy . Factors that are used to determine the risk of prostate cancer recurrence include the grade of the tumor , the extent to which the tumor has spread into surrounding tissue, and whether tumor cells are found in nearby lymph nodes during surgery.

The use of hormone therapy before prostatectomy has not been shown to be of benefit and is not a standard treatment. More intensive androgen blockade prior to prostatectomy is being studied in clinical trials.

Relapsed/recurrent prostate cancer. Hormone therapy used alone is the standard treatment for men who have a prostate cancer recurrence as documented by CT, MRI, or bone scan after treatment with radiation therapy or prostatectomy.

Hormone therapy is sometimes recommended for men who have a “biochemical” recurrencea rise in prostate-specific antigen level following primary local treatment with surgery or radiationespecially if the PSA level doubles in fewer than 3 months.

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Intermittent Versus Continuous Hormone Therapy

Most prostate cancers treated with hormone therapy become resistant to this treatment over a period of months or years. Some doctors believe that constant androgen suppression might not be needed, so they advise intermittent treatment. This can allow for a break from side effects like decreased energy, sexual problems, and hot flashes.

In one form of intermittent hormone therapy, treatment is stopped once the PSA drops to a very low level. If the PSA level begins to rise, the drugs are started again. Another form of intermittent therapy uses hormone therapy for fixed periods of time for example, 6 months on followed by 6 months off.

At this time, it isnt clear how this approach compares to continuous hormone therapy. Some studies have found that continuous therapy might help men live longer, but other studies have not found such a difference.

What Are The Medications Used For Androgen Deprivation Therapy

• Anti-androgens, such as bicalutamide, nilutamide, flutamide, enzalutamide, apalutamide, and darolutamide work by blocking testosterone receptors on prostate cancer cells.
• LHRH agonists such as goserelin, triptorelin, leuprolide mesylate, and leuprolide work by stopping the pituitary gland from making luteinizing hormone. Luteinizing hormone helps make testosterone. By stopping luteinizing hormone from being made, testosterone levels are lowered.
• A few other medications, such as relugolix and degarelix, LHRH antagonists, abiraterone acetate , and Ketoconazole , are also used as anti-androgen therapies in advanced prostate cancers, high-risk prostate cancer, and castrate-resistant prostate cancer.

Talk with your healthcare provider about the type of medication being prescribed for you.

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Adverse Events Of Lhrh Agonists

The adverse events associated with LHRH agonists can be categorized as immediate, acute, and chronic. The optimal use of ADT requires an effort to prevent or treat these adverse events.

One of the limitations of LHRH agonists is the initial flare phenomenon, which is attributed to a surge of serum testosterone levels due to the initial stimulation of LHRH receptors.13 The flare phenomenon may be life threatening if an LHRH agonist is administered to men with high-volume metastatic disease. The clinical consequence of the flare is prevented by pretreatment with an antiandrogen, which inhibits the stimulatory effect of the testosterone surge at the level of the androgen receptor.14

Men with advanced prostate cancer are also predisposed to developing anemia due to hematuria from locally advanced prostate cancer and to bone marrow infiltration by metastatic disease. Testosterone increases production of erythrogenesis-stimulating proteins.22 Therefore, LHRH agonists may cause or exacerbate anemia by indirectly inhibiting erythrogenesis.

Progressive muscle loss has been associated with declining testosterone levels in men.15 Men receiving LHRH agonists for prostate cancer demonstrate significant increases in muscle fatigue.23 Resistance exercises may limit the consequences of LHRH agonists on muscle function.