The growth and function of normal prostate cells depend on androgens (male sex hormones).The androgens, the main one that testosterone has to be, for the most part in the testes under the influence of the hormone LH formed. A small portion also comes from the adrenal glands (For details on all hormones and their regulation in the next picture and sex hormones ).
Also for the growth of malignant prostate cells, androgens play an important role (see sectioncauses ). Is effective that their artificial reduction in advanced prostate cancer, was first described in 1941, and Charles Huggins later got the Nobel Prize for this discovery. You can reach the goal in two ways, which are called, regardless of the then still existing as both androgen androgen deprivation (ADT or androgen deprivation therapy): Either by lowering androgen production by orchiectomy (removal of the testes), LH-RH analogues , LH -RH antagonists and estrogens , or by inhibition of androgen action with antiandrogens (all see next sections, starting points see picture).
Bilateral orchiectomy
This refers to the removal of both testicles, surgical castration . It is the oldest form of hormone therapy and is still performed sporadically, usually as a subcapsular orchiectomy , as enucleation of the androgen -producing tissue while leaving the testis and epididymis. Thus, the blood level of testosterone drops to the so-called castration levels of less than 50ng/dl.
Advantages are the low cost, relatively simple procedure, rapid and durable lowering hormone, and low need for frequent doctor visits. The disadvantages in comparison to the drug androgen deprivation (see next sections) are greater psychological distress, the fact that the procedure is irreversible, that is not reversible, and possible complications of surgery. It therefore comes today only in special cases to use (eg, for rapid relief of pain caused by metastases ). Side effects see Androgenentzugssyndrom .
LH-RH analogs
LH-RH analogs are drugs that act the same as LH-RH (similar to this), which is why they are also called LHRH agonists (competitors). Your continued use initially leads to a release of LH from the pituitary gland and thus to an increase in androgen (flare-up phenomenon after 2-3 days for about 7 days; see figure above). Because of the continuous stimulation of the pituitary gland is it then but the so-called medical castration: The LH-RH receptors number of pituitary gland decreases, so that it is insensitive to LH-RH, drops the release of LH and androgen levels after 2-4 weeks castrate levels decreases (testosterone less than 50ng/dl).
The active ingredients are injected in the form of deposits under the skin or into the muscle. All preparations have similar or the same active qualities. However, they differ in the duration of action of the depot (one, two, three, six or twelve months) and thus in the number of injections required per year. There are also differences in the dosage form (eg liquid or solid suspension rods = implant), which determines the thickness of the needle required for spraying. Because the initial Androgenanstiegs can in the first 2-4 weeks in addition an antiandrogen (see beloware) added, especially in very advanced tumor.
Treatment with LH-RH analogues is now considered standard in all forms of hormone therapy. It is as effective as orchiectomy, but in contrast to this (undo) reversible, ie after cessation of LH-RH analogues androgen production is in most men again. The psychological stress associated with the removal of the testicles addition is not necessary. Otherwise, the possible side effects are comparable (see below ).
LH-RH antagonists
These drugs are the "opponent" of the natural LH-RH : they block the receptors on the pituitary gland (see figure above). After initial studies they seem to be equally effective as LH-RH analogues. In contrast to this, they have no initial Androgenanstieg, but a faster decrease of androgens to castrate levels result, and are only available as a 1-month depot. Their use is currently limited, also because of possible severe allergies and the lack of long-term results.Other side effects correct to the current state of knowledge which the LH-RH analogues and orchiectomy (see below ).
Estrogens
Estrogens (female sex hormones) are formed in small quantities in the art and are for his body very important (see also sex hormones ). In higher doses used for the treatment they act through different mechanisms, including via inhibition of LH-RH release and thus a reduction in androgen to castration levels after 3-9 weeks (see figure above). They were the first possibility of medical castration as a substitute for the orchiectomy and were found to be equally effective.In addition to the expected side effects (see below ) were dose-dependent but also increasingly those of the cardiovascular system, so that one estrogens rarely used today.
Antiandrogens
All antiandrogens block the receptors of androgens on the target cells and thus prevent their effects (see figure above). Administered as a tablet and classified according to their structure into steroidal and non-steroidal antiandrogens:
Steroidal antiandrogens: These drugs contain a so-called steroid backbone. They block the action of androgens and additionally reduce their blood levels by inhibiting the LH release from the pituitary. Of the available agents, the cyproterone acetate (CPA) is the best-studied: The androgen levels fall rapidly to about a quarter, but not to the castration level. However, the side effects are similar to orchiectomy (see below ), with loss of libido and erectile dysfunction occur frequently, gynecomastia, however, is rare. CPA alone appears to be less active than LH-RH analogues and orchiectomy, but similar non-steroidal antiandrogens (see next paragraph). It is used especially at the beginning of an LH-RH analogue therapy (because of the initial Androgenanstiegs, see above ) and - to a lesser dose - for the prevention of hot flashes in otherwise hormone therapy.
Non-steroidal antiandrogens: you only block the action of androgens. Is also affected those on the brain, which normally ensures that less LH distributed and therefore the production of androgens is slowed (see also sex hormones ). The androgen levels can therefore increase slightly, but mostly remains the same. The side effects are different from those of orchiectomy and the other drugs (see next paragraph ): libido , erection , physical performance and bone density should not be affected most. Frequently, however, there is pain and enlargement of the mammary gland. Prophylactic irradiation of the mammary gland is considered here as an effective therapy. Other side effects depend on the drug. These drugs are mainly used as monotherapy at the maximum androgen blockade (both see next paragraphs), and at the beginning of therapy with LH-RH analogues (see above ).
Androgenentzugssyndrom
This term summarizes the side effects of hormone reduction together. Depending on the method and agent various undesirable effects may occur (see also in the previous paragraphs). About the most common and their treatment options, the patient should be advised:
- Hot flashes (german hot flush, hot flash) and sweats. Treatment: medications (eg cyproterone acetate, an antiandrogen, see also above )
- Loss of libido ("Lust")
- Erectile Dysfunction. S treatment erectile dysfunction
- Pain and enlargement (gynecomastia), breast disorders (mainly in the treatment with anti-androgens, see above ). Treatment: Preventive radiation or surgery, possibly drugs
- Weight gain, muscle loss, metabolic changes, may increase the risk for cardiovascular disease. Treatment: exercise, muscle training, diet
- Anemia (anemia) may result in, among other things to weakness, fatigue and shortness of breath. Treatment: blood transfusion, possibly drugs
- Bone loss (osteoporosis), increases the risk of bone fractures. Treatment: motion training, calcium, vitamin D, drug
Monotherapy: Usually, only one method is initially applied (monotherapy), mostly as continuous androgen deprivation with an LH-RH analogue, more rarely by orchiectomy , LH-RH antagonist, or a non-steroidal antiandrogen. Because of the side effects, also in terms of sexual function, other treatment options were examined as the intermittent and deferred androgen deprivation (see next paragraphs).
Maximum androgen blockade (MAB): They are also called complete androgen blockade (engl. complete androgen blockade, CAB). Not only the androgen is turned off in the testes, but also the effect of the remaining, formed in the adrenal androgens blocked (5-10%, see also sex hormones ). MAB usually includes a combination of an LHRH analogue and a non-steroidal anti-androgen. Studies suggest that in the MAB experience more side effects than monotherapy.
Triple therapy (from engl triple = three times.): Controversial treatment with a combination of LH-RH analogue, non steroidal antiandrogen and 5-alpha-reductase inhibitors , which are both omits to therapy, the first after the response and progression of the tumor is back, so used intermittently.
Continuous or intermittent androgen deprivation? The effect of continuous androgen deprivation (engl. continuous androgen deprivation CAD) deteriorates with time after, the tumor becomes androgen-independent (see below ). The intermittent (sometimes interrupted) androgen deprivation (English intermittent androgen deprivation, IAD), who after a naturallyorchiectomy is not possible, has the goal to prolong survival and at the same time to reduce the side effects (eg on sexual function). To do this go a lower and an upper limit for the PSA fixed value and leads to androgen deprivation by only until the PSA level reaches the lower limit. If the value rising again and exceed the upper limit, the therapy is continued. So half the time is on average therapy-free, in the androgen rises again, the side effects go back and the quality of life increases. Currently, the intermittent androgen deprivation is considered as effective as the continuous. However, some important questions are still unclear, and there are no long-term data before (eg for survival).
Immediate or deferred androgen deprivation: The optimal time to start hormonal therapy is not yet clear in all cases. It provides, for example, the question of whether these in a patient with prostate cancer who already metastases , can be deferred without risk has formed, but still does not cause symptoms in order to avoid the side effects of the therapy for now.
Supportive (neoadjuvant and adjuvant) hormone therapy: It is used in conjunction with another first-line treatment and is already in the sections radical prostatectomy and radiation therapy described.
Hormone therapy during non-metastatic prostate cancer
In prostate cancer without metastases (secondary tumors) is called, depending on its local expansion of a localized or locally advanced prostate cancer (T1-2 N0 M0 or T3-4 N0 M0, the TNM system see section growth and spread ). Rate should be curative (aiming at healing) treatment ( active surveillance , radical prostatectomy or radiation therapy ; see also the section treatment planning ). To hormone therapy in connection with the operation, see the section "radical prostatectomy" under adjuvant therapy . To hormone therapy in conjunction with radiation therapy, see there under locally limited prostate cancer and locally advanced prostate cancer .
Decides a patient with a localized or locally advanced prostate cancer is not a curative, but for a palliative (palliative) treatment, you can immediately initiate hormone therapy or initially hesitant to watch him (For details on the information and decision-making see sectionexpectant observation ).
In case a patient with localized prostate cancer from a curative therapy, hormone therapy can be offered to him after detailed reconnaissance. If a patient obtained with a locally advanced tumor such therapy, it can by surgical or medical castration (eg with bilateral orchiectomy, LH-RH analogue, LH-RH antagonist, all above) or with an antiandrogen (for example bicalutamide 150mg per day) are treated.
Hormone therapy for metastatic prostate cancer
From a metastatic prostate cancer is when the regionären (local) lymph nodes (N1), or ifmetastases (secondary tumors) are present in distant lymph nodes or to other parts of the body (M1; to the TNM system see section growth and spread ) .
A lymph node involvement can be explained by a lymphadenectomy prove (removal) in radical prostatectomy or in a separate engagement with subsequent histological (histologic) examination. If this is the case and there are no other metastases (pN1 M0), are used as local treatment of the tumor , radical prostatectomy or radiation therapy in question and as asystemic (general) treatment for the immediate or deferred hormonal therapy (see also the section "Treatment Planning" with lymph node involvement ). The choice has to be made individually, because there is currently no reliable comparison of these methods, either alone or in combination. The same applies if a removal is not possible and the infection risk is assessed as high. In an already clinically recognizable lymph node involvement (cN1, eg imaging) is to be expected with metastases at other locations (M1, see over the next paragraph). More to hormone therapy when lymph node involvement without metastases see "radical prostatectomy" under adjuvant therapy and the "radiation therapy" under lymph node involvement .
In a relapse (recurrence) of prostate cancer after curative (healing on-targeting), initial treatment may come into question also hormone therapy. See sections "treatment planning" inrelapsed prostate cancer , "radical prostatectomy" under relapse therapy and "radiotherapy" among relapsed .
In metastatic prostate cancer, patients should be informed of the hormone therapy, especially about having to palliative (soothing) is that they can affect quality of life, what adverse effects are possible and that, although the time to progression with immediate therapy tumor (PFS) extended, but it is still unclear whether this (overall survival) also applies to the time to death.
Patients who already have symptoms have (symptoms), will then be recommended (immediate) hormone therapy, patients without symptoms, the (immediate or deferred) hormone therapy offered (also refer to the section "Treatment planning" under distant metastases ). If an androgen indicated, he should surgery (bilateral orchiectomy with see above take place) or with medication (LH-RH analogues, LH-RH antagonists, no monotherapy with steroidal antiandrogens, all see above ).
Alternatively, patients with metastatic prostate cancer therapy are offered with a non-steroidal antiandrogen (see above ). They should first be advised what side effects are possible compared to the hormone reduce sexual interest and physical performance are less affected and that the overall survival time is shorter in this treatment. The latter could also apply only to patients with extensive metastases.
The maximum androgen blockade (MAB see, above ) can be used as first-line treatment used.Studies suggest a small survival benefit compared to monotherapy with hormone reduction, but with more side effects. Similarly, after being informed of the missing long-term data, intermittent androgen deprivation (IAD, see above ) can be performed.
Progressive prostate cancer hormone therapy
Prostate speaks in most cases (80-90%) initially on the hormone therapy, recognized by improved symptoms, a reduction of the tumor and the waste of PSA value and testosteroneblood levels (to the castration level of less than 50ng/dl) . For reasons not completely clarified reasons he advances still continues after a few years, as demonstrated by the re-increase of the PSA value or signs of disease, usually shows bone pain.
Although the tumor was previously apparently not completely eliminated, it still speaks of arelapse (recurrence of the disease), and that at a PSA rise again of a biochemical recurrence (BCR, laboratory signs of a recurrence), while continuing to grow at the original site of a local recurrence (tumor recurrence) and in the growth of metastases to lymph nodes or other parts of the body of a systemic recurrence.
Because the tumor progresses at a suppressed androgen levels, it is called androgen-independent or androgen-insensitive prostate cancer. However, he still usually reacts to changes in androgen deprivation and the administration of other hormone-effective drugs, a so-called secondary hormonal manipulation :
- Maximum androgen blockade (MAB, if not already done, see above ) with an LH-RH analogue (or by means of orchiectomy ) and an antiandrogen
- Maximum Antiandrogendosis (if not already done)
- Discontinuation of the antiandrogen: This effect is called antiandrogen withdrawal syndrome, the mechanism is still unclear
- Other hormone-effective medicines (eg, corticosteroids, possibly ketoconazole, aminoglutethimide, estrogens , somatostatin analogs, etc.)
Treatment of progressive prostate cancer on hormonal reduction: First, to thetestosterone levels are monitored to check whether the treatment current is suppressed sufficiently and the androgens tumor actually androgen independent. Then the patient should be informed that a cure is not possible, a secondary hormonal manipulation (see above) or additional chemotherapy can relieve the symptoms, chemotherapy or second-line treatment with abiraterone (both see Section chemotherapy ) is the survival time by an average of some extended months, the treatments can have side effects and the impact on quality of life are insufficiently investigated. In the treatment decision should be considered: complaints, comorbidities, life expectancy, quality of life and wishes of the person concerned, side effects of the individual treatments, rate of progression of the tumor and localization of metastases and tumor burden (amount of cancer). For the first-line treatment (first further treatment), the following applies:
First-line therapy in patients without symptoms: One can offer the patient the waiting below the previous androgen deprivation and the secondary hormonal manipulation (see above). How does the discontinuation of androgen deprivation effect has not yet been adequately studied. The patient should be informed before deciding that this is palliative is (palliative) treatment that maximum androgen blockade (see above ) has additional side effects and that for the secondary hormonal manipulation without prior chemotherapy had a prolonged survival has not been demonstrated. You can him also offer chemotherapy when the PSA value increases rapidly (doubling time = PSA-DT less than 3 months), when the progression was detected by imaging techniques or if the patient wishes this treatment for rising PSA level. It has not been proven that early chemotherapy, which begins, as long as there are no complaints, longer survival has the result than if you only when symptoms initiates (see section Morechemotherapy ).
First-line treatment in patients with symptoms: Treatment options and the next steps will be discussed and determined by physicians of all relevant disciplines. The patient should be informed before deciding that this is palliative is (palliative) treatment, only in a subset of patients perform the therapies to relieve the symptoms or a prolongation of life and chemotherapy more side effects than hormone therapy or the gift of corticosteroids. Depending on the results you can offer:
- Hormone therapy
- Corticosteroids (see above)
- Chemotherapy
- Treatment of symptoms (Supportive, see section palliative care )
- Treatment of bone metastases (see section palliative care )
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