Luteinizing Hormone Releasing Hormone Prostate Cancer

Intermittent Versus Continuous Hormone Therapy

Disease Flare with LHRH Agonists is a Myth

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.

Lhrh Lhrh Receptors And Cancer

LHRH, also known as GnRH, is a hormonal decapeptide produced by the hypothalamus, which plays a pivotal role in the regulation of the pituitary/gonadal axis, and thus, reproduction . Its effects are exerted through binding to high-affinity receptors on the pituitary gonadotroph cells and subsequent release of FSH and LH . Physiological studies with LHRH or its superactive agonistic analogs in patients revealed that chronic treatment with these hormones results in desensitization of the pituitary gonadotropes, and in turn, a suppression of sex steroid production by the gonads .

Because sex steroids have been implicated in the development of breast and prostate cancers, studies were initiated in patients for the treatment of these malignancies with LHRH agonists. Based on these clinical studies, hormonal therapy with LHRH agonists was approved for the treatment of sex-steroid-dependent conditions, including estrogen-dependent breast cancers and androgen-dependent prostate carcinoma . Although the basic mechanism of action of LHRH analogs on cancerous cells was initially assumed to be indirect, through the suppression of sex steroids, antiproliferative action of these peptide hormones on human breast cancer cell lines in vitro suggested an additional, direct effect, mediated by tumoral LHRH receptors .

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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The Clinical Effectiveness Of Lhrh Agonists In Prostate Cancer

LHRH agonists do not work in every patient with advanced prostate cancer. Some patients just do not respond sufficiently to treatment with LHRH agonists because their disease has already progressed too far. Others are among the unfortunate minority of patients who are unable to tolerate LHRH agonist therapy because they suffer severe side effects to these drugs.

Having said that, the vast majority of prostate cancer patient will respond relatively well to LHRH agonist therapy, and generally for considerable periods of time.

For various reasons discussed elsewhere on this web site, many men today start to receive LHRH agonist therapy long before they have any specific evidence of metatstatic prostate cancer, and it is not uncommon to come across men who have received hormone therapy either continuously or intermittently for 10 years or more. It is also true that some men may be able to stop hormone therapy entirely after a period of time, with a low and stable PSA. We do not know why this appears to be possible for some men and not for others.

In most cases, men with prostate cancer will start to develop an increasing number of prostate cancer cells that are not responsive to hromone therapy, and there will come a point in time when their PSA starts to rise again regardless of LHRH and other forms of hormone therapy. These men have a form of the disease known as hormone refractory prostate cancer, which is a terminal stage of the disease.

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What Is Intermittent Adt

Researchers have investigated whether a technique called intermittent androgen deprivation can delay the development of hormone resistance. With intermittent androgen deprivation, hormone therapy is given in cycles with breaks between drug administrations, rather than continuously. An additional potential benefit of this approach is that the temporary break from the side effects of hormone therapy may improve a mans quality of life.

Randomized clinical trials have shown similar overall survival with continuous ADT or intermittent ADT among men with metastatic or recurrent prostate cancer, with a reduction in some side effects for intermittent ADT .

Treating Prostate Cancer With Hormone Therapy

Hormone therapy, also known as androgen deprivation therapy , has long been the backbone of treatment for metastatic prostate cancer.

The male sex hormone testosterone is known to stimulate the growth of prostate cancer cells.

Hormone therapy, depending on the form, reduces this effect by either decreasing the bodys production of testosterone or blocking testosterone from binding to cancer cells.

There are several scenarios in which hormone therapy is typically used:

When prostate cancer has spread too far to be cured by surgery or radiation, or has recurred after surgical or radiation treatment
As an initial treatment for patients who are at higher risk of recurrence after treatment, such as those with a high PSA level or a high Gleason score
For patients who have a high PSA level following surgery or radiation, even if they have no evidence of disease. Not all doctors, however, agree with this approach

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Treatment By Stage Of Prostate Cancer

Hormone Therapy for Prostate Cancer

Different treatments may be recommended for each stage of prostate cancer. Your doctor will work with you to develop a specific treatment plan based on the cancers stage and other factors. Detailed descriptions of each type of treatment are provided earlier on this same page. Clinical trials may also be a treatment option for each stage.

Early-stage prostate cancer

Early-stage prostate cancer usually grows very slowly and may take years to cause any symptoms or other health problems, if it ever does at all. As a result, active surveillance or watchful waiting may be recommended. Radiation therapy or surgery may also be suggested, as well as treatment in clinical trials. For those with a higher Gleason score, the cancer may be faster growing, so radical prostatectomy and radiation therapy are often recommended. Your doctor will consider your age and general health before recommending a treatment plan.

ASCO, the American Urological Association, American Society of Radiation Oncology, and the Society of Urologic Oncology recommend that patients with high-risk early-stage prostate cancer that has not spread to other areas of the body should receive radical prostatectomy or radiation therapy with hormonal therapy as standard treatment options.

Locally advanced prostate cancer

Watchful waiting may be considered for older adults who are not expected to live for a long time and whose cancer is not causing symptoms or for those who have another, more serious illness.

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Gnrh Agonist Vs Gnrh Antagonist

The decision to use a GNRH agonist vs antagonist depends on several factors. Given the shorter time to testosterone suppression and lack of testosterone surge, GNRH antagonists may be more clinically beneficial for patients with more advanced disease and at higher risk of developing prostate cancerrelated symptoms.13 Additionally, the absence of tumor flare with GNRH antagonists may seem especially appealing in patients with impending cord compression or urethral obstruction however, GNRH agonists in conjunction with antiandrogen agents for flare prophylaxis have been shown to achieve similar effects.14

From a practical standpoint, degarelix is given on a monthly basis compared to the less frequent dosing options of GNRH agonists. With oral relugolix, issues of compliance and the likely need for continual testosterone monitoring are possible barriers that are not routinely of concern for patients receiving injection therapy.

Adverse effect profiles also play a large role in the selection of a GNRH agonist or antagonist. Both the phase 3 degarelix trial and the HERO trial showed that adverse events were similar across all treatment groups, with flushing/hot flashes being the most common AE. Relugolix had increased reports of diarrhea compared with leuprolide.6 Leuprolide had higher rates of arthralgia and urinary tract infection compared with degarelix, whereas degarelix was associated with more injection-site reactions.5

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 byCT, 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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Lhrh Antagonists Vs Lhrh Agonists: Which Is More Beneficial In Prostate Cancer Therapy

Oncology

Crawford and Hou review the data on luteinizing hormone-releasing hormone antagonists in prostate cancer. They describe the results of a phase III trial comparing monthly degarelix to monthly leuprolide in men with advanced prostate cancer. Degarelix treatment was associated with a more rapid decline of serum testosterone, and was not associated with an initial surge of serum testosterone seen during the first few days of treatment with leuprolide. They discuss the role of this new form of medical gonadal suppression for the treatment of prostate cancer.

How Effective Is Hormone Therapy For Prostate Cancer

In the initial years of diagnosis, hormone therapy for prostate cancer can help patients with their symptoms and add years to their lives.

For men who need hormone therapy, such as men whose prostate-specific antigen levels are rising after surgery or radiation or men with advanced prostate cancer who dont yet have symptoms, its not always clear when the best time is to start hormone treatment:

Some doctors think that hormone therapy works better if its started as soon as possible, even if the patient feels well and is not exhibiting any symptoms. Studies have shown that hormone treatment may slow down the disease and perhaps even help men live longer.
Some doctors, however, donât agree with this approach. Because of the side effects and the risk of the cancer becoming resistant to therapy sooner, some doctors feel that treatment should not be started until cancer symptoms appear.

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Surgery To Remove The Testicles

You may be offered an operation to remove the testicles, or the parts of the testicles that make testosterone. This is called an orchidectomy . Its not used as often as other types of hormone therapy.

Surgery is very effective at reducing testosterone levels, which should drop to their lowest level very quickly usually in less than 12 hours. It also means that you wont need to have regular injections, so theres no risk that youll miss an injection.

Surgery cant be reversed, so its usually only offered to men who need long-term hormone therapy.

If youre thinking about having surgery, your doctor may suggest trying injections or implants for a while first. This will give you and your doctor a chance to see how you deal with the side effects of low testosterone.

Short-term side effects of an orchidectomy include swelling and bruising of the scrotum .

Some men find the thought of having an orchidectomy upsetting and worry about how theyll feel once their testicles are removed. Speak to your doctor if you have any concerns.

If you dont want an orchidectomy, you can usually have a different type of hormone therapy instead.

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Questions To Ask Your Doctor Or Nurse

What is the aim of treatment?
What type of hormone therapy are you recommending for me and why?
How often will I have my injections or implants?
How will my treatment be monitored?
How long will it be before we know if the hormone therapy is working?
What are the possible side effects, and how long will they last?
What will happen if I decide to stop my treatment?
Are there any clinical trials that I could take part in?

Advantages And Disadvantages Of Lhrh Agonists

Enzalutamide preferable to bicalutamide plus LHRH analogue in prostate cancer

Introduced in the United States in 1984, LHRH agonists essentially deplete the pituitary hormone and downregulate pituitary LHRH receptors, rendering the pituitary nonresponsive to further stimulation by LHRH. Currently available LHRH agonists include leuprolide, goserelin , buserelin, and triptorelin . Available in various formulations, these drugs are administered via depot injections that last as long as 12 months.

However, disadvantages of LHRH agonists include high repeating costs, libido loss, impotence, and hot flashes. Importantly, the testosterone surge that occurs after initial injection of LHRH agonists can cause tumor flare in up to 63% of patients with advanced disease. In certain men with advanced prostate cancer, these flares are accompanied by pain and serious side effects that can include urethral obstruction and spinal cord compression, which can lead to paralysis and, rarely, death. Accordingly, oncologists frequently administer short-term or long-term antiandrogens to prevent testosterone surge in patients taking LHRH agonists.

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How Effective Is Hormone Therapy At Treating Prostate Cancer

While hormone therapy cant cure your prostate cancer, it can stop or slow the growth of the prostate cancer cells in your body. Hormone therapy is remarkably effective, says Dr. Ornstein. Probably over 90 percent of patients will have a nice drop in their PSA while they are on androgen deprivation therapy. The cancer should not grow or spread, because there is no more fuel, he explains.

In many men, however, some cells gain the ability to grow even in the low-testosterone environment created by hormone therapy. As these hormone therapy-resistant prostate cancer cells continue to multiply, the hormone therapy, not surprisingly, has less and less effect on the growth of the tumor.

Prostate cancer that is no longer responding to hormone therapy is referred to as castration-resistant prostate cancer.

Fortunately, men with castration-resistant prostate cancer have more options for treatment than ever before. At that point, we can add something new, such as a newer hormonal agent, chemotherapy, or a different chemotherapy, if you had one up front, or an immunotherapy, explains Ornstein.