The hormonodependence of certain tumours has for a long time been demonstrated.
It is known, for example, since the end of nineteenth century, that bilateral ovariectomy improves breast cancer.
In 1941, Higgins demonstrated that bilateral castration considerably improved metastatic bone pain in prostate cancer sufferers. It is has also been acknowledged for many years that castrated men never develop prostate carcinoma.
Def: Hormonal therapy is one of the major modalities of medical treatment for cancer, others being cytotoxic chemotherapy and targeted therapy (biotherapeutics). It involves the manipulation of the endocrine system through exogenous administration of specific hormones, particularly steroid hormones, or drugs which inhibit the production or activity of such hormones (hormone antagonists). Because steroid hormones are powerful drivers of gene expression in certain cancer cells, changing the levels or activity of certain hormones can cause certain cancers to cease growing, or even undergo cell death. Surgical removal of endocrine organs, such as orchiectomy and oophorectomy can also be employed as a form of hormonal therapy.
In practice, we can study the following cancers as hormonodependent:
Hormone receptors :
Steroid hormones (from vitamin D to suprarenal hormones) act by their fixation to a specific receptor situated inside the cell nucleus. The complex is a DNA transcription factor which induces various protein syntheses. Steroid receptors are proteins from 427 to 984 amino acids with many analogical zones from one species to another and from one receptor type to another.
Receptors are active in several domains:
Progesterone receptors are synthesised after the action of oestrogens and thus reflect the actions of both oestrogens and progesterone on tumour cells.
The presence of receptors is a good prognostic factor: breast cancer patients with positive receptors have a longer survival without relapse than patients without detectable receptors.
There has been less study on receptors for prostate cancer. The conversion of testosterone by the prostate cell via a 5- α reductase, enables the reduced hormonal molecule to penetrate into the nucleus.
Hormonal therapy is based on the possibilities of breaking the interaction between testosterone or its derivative with its receptors, thus reducing the transcription factors induced by the combination of the hormone and its receptor.
Mechanisms of action :
The mechanisms of action of the various hormonal treatments correspond to one of the following:
Disappearance of the stimulating hormone,
Action of an antihormone acting of the receptor,
Inhibition of the synthesis of the stimulating hormone or of its active derivate.
For breast carcinoma, the 5-a reductase is replaced by the action of anti-aromatase, with a relatively similar effect (inhibition of synthesis).
The following pages describe the actions of the various products (or techniques) used in daily clinical practice.
Castration :
However, it still constitutes an excellent treatment modality for breast cancer bone metastases (if no previous treatment with antioestrogens has been administered): a very powerful and rapid analgesic effect is generally obtained with tumour regression and often prolonged survival.
There are major side effects among young non-menopaused women, due to the abrupt menopause induced by castration and its often severe psychological consequences.
They induce a castration effect by blocking hypothalamus hormones.
The virilisation observed in long_term treatment, together with the risks of hypertension and the appearance of new drugs, far better tolerated by patients, have led to the disappearance of androgens from the therapeutical repertoire, except (perhaps) in pre-terminal phases when their anabolising effect can be useful (improved appetite, lesser asthenia).
The most frequently used drugs were diethylstilbestrol as well as estradiol di-undecylate (or Oestradiol –Depot ).
They have peripheral side effects which are symptoms of feminisation: gynaecomastia, altered repartition of fatty tissue), however their main action consists in blocking the secretion of the hypothalamus hormone LH RH, thus inducing a suppression of LH by the pituitary gland and secondarily of testosterone by the testis.
Chemical castration is therefore obtained without hot flushes.
Oestrogens (especially at high prolonged dosages 3mg/d) have been abandoned because of the thrombosis and embolism complications that they induce and which diminish the positive effect of the treatment in randomised studies. Unfortunately, a dosage of 1 mg/d may not be sufficient for all patients. Thus, (at least in France), oestrogens are no longer a first-line hormonal treatment for prostate cancer.
Following the failure of first-line hormonal treatment, DES may offer significant responses.
Oestrogens can also be used in a loading dose (for acute complications which are not amenable to surgery or radiotherapy, such as diffuse medullar compression or very intense pain).
Fosfetrol (or ST 52) is a prodrug which brings the active agent to the prostate. Dephosphorylation induces the formation of the active metabolite: diethylstilbestrol (DES). Due to the presence of acid phosphatases, Fosfetrol is mainly (but not solely) transformed at the tumour site, which avoids general oestrogen treatment and a much higher dosage to the prostate, thus limiting the risk of gynaecomastia, thrombosis and pulmonary embolism.
Moreover, as for oestrogens, the inhibition of the hypothalamus-pituitary axis is observed, thus reducing the testicular synthesis of androgens.
Agonists of LH-RH :
The synthesis of numerous LHRH analogues and the production of easy to use galenic forms (injections with depot properties) has transformed the hormonotherapy of prostate cancer (and to a lesser extent breast cancer)
These drugs have many non-cancer-related indications (endometriosis, uterine fibroma, ovarian polycystosis, hirsutism).
The main drugs are:
The pituitary cells, will initially respond to the stimulation of hypothalamic hormone analogues by increased LHRH secretion. The testis will respond to this secretion by increased testosterone synthesis.
It is very important to be aware of the ‘flush’ effect, since, at the beginning of treatment, it may lead to the aggravation of pain, paralysis or prostate symptoms.
Treatment by LHRH agonists should therefore not be initiated without previous antiandrogen treatment (or antioestrogen for breast cancer) over a few days.
It is quite possible that these agonists have a direct action on tumour cells, since rare observations of responses in castrated men (or women) have been described.
The secondary effect of agonists involves chemical castration by the exhaustion of the pituitary gland. Hot flushes are frequently observed and castration leads to impotence (in almost all patients), loss of libido and major hypogonadism.
One of the constraints of this treatment is the necessity to indefinitely pursue the monthly (or tri-monthly) subcutaneous injection. If the treatment is stopped, the castration effect will slowly regress (in particular when treatment duration is short).
In prostate cancer, up to 70% of remissions are obtained using this treatment and their mean duration is around one to three years (and much longer among certain patients).
In breast cancer, this treatment is often instituted in order to obtain non-definitive castration for young patients in the hope of a return of normal menstruation.
Antiandrogens :
Antiandrogens are very powerful drugs which act on the androgen receptor and are used to treat metastatic prostate carcinoma.
We can distinguish two categories of anti-androgens:
The side effects of this product are either related to hormonal deficiency (loss of libido, impotence, asthenia, moderate gynaecomastia) or to vascular disorders (venous thrombosis) or, more rarely, liver toxicity (cytolysis).
There is no testosterone concentration diminution: thus no hot flushes, no or limited loss of libido and a variable diminution of sexual potency.
The most toxic side effect is gynaecomastia (which may be painful) in approximately 60% of patients, diarrhoea, vomiting, modification of liver enzymes and visual disorders for one drug (nilutamide).
A relatively high number of molecules are available:
Progestative drugs :
The presence of progesterone receptors in breast cancer cells and in endometrial cancer cells has led to the use of progestative drugs for advanced or metastatic cancer.
In metastatic corpus uteri cancer (more than 80% of patients are cured with local treatment), progestative drugs give a response rate of around 30% for patients with a progesterone receptor and less than 10% for others. This treatment is generally very well tolerated, hence its prescription in all palliative situations before chemotherapy, which is not very efficient.
In breast carcinoma, the progestative molecules (such as megestrol acetate) are prescribed as second-line hormonotherapy: their efficiency is proportional to the efficiency of first–line hormonotherapy (generally tamoxifen).
Progesterone also has a positive effect on appetite and general status (as for cortisone and androgens) but it can induce hydric retention.
Progesterone dosage for this indication is rather high. The following drugs are available:
Aminoglutethimide :
Aromatase is an enzyme which catalyses three hydroxylations which are necessary for the metabolism of steroidal hormones from cholesterol. It is present in great quantities in the adrenal gland and ovaries, and most probably in other tissues (present in mammary cells).
Aminoglutethimide acts in the same manner as chemical adrenalectomy, i.e. blocks the synthesis of minor androgens and oestrogens by the adrenal gland. It also disturbs the synthesis of hydrocortisone, thus, in order to avoid Addison’s disease, small doses of hydrocortisone should be simultaneously administered.
In breast cancer, the response rate (as second-line hormonotherapy) is approximately 20-30%. In prostate cancer, the same indication gives a response rate of around 15-20%.
The above diagram clearly shows that, in prostate cancer, the main source of testosterone remains unaltered by aminoglutethimide and that castration (either surgical or medical) should be continued in order to avoid a rebound effect.
Antiaromatase drugs :
Ovarian aromatase plays the same major role as adrenal aromatase in oestrogen synthesis.
The ovary, as an endocrine gland, can be considered as having two compartments: the interstitial or stromal compartment which is under the influence of LH, controls the synthesis of androstene dione by stroma cells. In the thecal compartment, granulosa cells, under the influence of FSH, regulate the quantity of aromatase in order to synthesise oestrone and oestradiol. The level of aromatase at ovulation is 8 to 10 times higher than during menstruation.
After menopause, the androgens originating from the adrenal gland (androstenedione, testosterone) are converted into oestrogens by the liver, muscle, hair, adipose tissue and tumour cell aromatase. Aromatase inhibitors stop this oestrogen production.
Antiaromatase drugs therefore play an essential role in the treatment of breast carcinoma, since they halt the production of oestrgens. Prescription of substitutive hydrocortisone (as in treatment by aminogluthetimide) is not necessary.
New synthetic antiaromatase drugs are currently manufactured: they act by direct competition with the enzyme (derived from imidazole) and directly prevent the transformation of androgens into oestrogens (particularly inside tumour cells).
There are two types of antiaromatase drug:
Side effects of these drugs, as reported to date, would appear to be relatively infrequent and are generally benign. However, osteoporosis may be a serious problem for women taking antiaromatase over a long period of time.
In breast cancer, antiaromatases are very efficient with at least a 35% response rate as first-line hormonotherapy among metastatic patients.
The comparison between anastrozole or letrozole with tamoxifen reveals a similar efficiency against cancer cells, however the toxicity profile is lower with no risk of thrombosis or embolism, and no risk of secondary endometrial cancer. Osteoporosis is an added complication which has not yet been completely evaluated. Thus, for many oncologists, antiaromatases are an interesting alternative to antioestrogens.
Adjuvant hormonotherapy :
This was clearly demonstrated by meta-analysis carried out it 1988 which revealed patient benefit independently of node status. The decreased risk of relapse was more significant during the first 5 years than during the following 5 years. However, a decrease in death rate was also systematically observed.
Consensus conferences by the NIH recommend the prescription of antioestrogens for all women with positive receptors, without taking into account tumour size or node status.
There is also a ±50% decrease in the risk of second breast cancer (controlateral) during the first five years, even when the tumour does not bear receptors.
The prolonged and systematic prescription of tamoxifen is limited by the increased risk of corpus uteri cancer (despite the fact that it is very often a minor and surgically curable cancer).
In the future, antiaromatase drugs may have an equivalent role in this adjuvant setting (but at a much higher cost), but our experience is, as yet, insufficient for us to be totally certain of this role. We are unaware of the exact incidence and gravity of potentially induced osteoporosis.
Ovarian suppression (for non-menopaused women), in an adjuvant setting, would also appear to be beneficial (reduction in relapse of 13%) and a probable increase in survival Although most meta-analyses have been developed with surgical or radiotherapic castration, it seems logical that ovarian suppression induced by LHRH agonists will offer the same benefits. These drugs have the advantage of enabling non-definitive castration, which is a very important point for young women who may desire pregnancy at distance from their cancer treatment.
In locally advanced disease (T3 with elevated Gleason histological grade or high levels of PSA), Bolla demonstrated a clear advantage in the simultaneous association of radiotherapy and hormonotherapy which should be prescribed for at least 3 years. There is no data for smaller stages.
For these patients, hormonotherapy carries an impotence risk close to 100%, whereas sexual potency (possibly with the help of Viagra) may resist radiotherapy.
Hormonotherapy for metastases :
Hormonotherapy is generally well tolerated. Treatment should begin with tamoxifen or an antiaromatase drug. The effect is produced within a few days or a few weeks. Hormonotherapy may be associated with other specific treatment modalities such as bone radiotherapy or surgery. Patients relapsing after tamoxifen may still obtain a good response with an aromatase inhibitor.
For pre-menopausal women, tamoxifen offers more or less the same efficiency as castration: the response duration (which is not, unfortunately, constant) is generally greater than one year, but can be much longer. For young patients, castration is performed at relapse. Antiaromatase drugs are not particularly efficient due to their high level of ovarian oestrogens (except after castration). The general use of chemotherapy, with its high response rate, sometimes clouds the value of hormonotherapy in terms of patient comfort.
Bone metastases are often very sensitive to hormonotherapy (pain reduction) although it may be difficult to establish the objective responses.
When metastases develop under hormonotherapy, it should be concluded that the tumour is hormonoindependent and chemotherapy should be attempted.
Surgical castration is the easiest and less expensive treatment. However, psychologically, it is often very poorly tolerated. However, its effect, (particularly for painful bone metastases) can be quite spectacular with patients experiencing no pain as early as the day after surgery. Of course, the androgenic deprivation cannot correct mechanical disorders (such as medullar compression or pre-fracture syndrome for which a surgical solution may be sought).
LHRH agonists (after a short period of antiandrogen treatment) is now the preferred chemical castration method, in a more expansive and elegant manner. Treatment should be pursued without interruption, even when the tumour becomes hormono-independent, otherwise hormone-dependent clones may reoccur. The side effects of surgical and chemical castration are identical.
Oestrogens are rarely prescribed (in correlation with their cardiovascular toxicity). They can, however, be useful if an acute metastasis occurs (with associated local treatment if necessary).
Many trials are underway in order to precisely define the role of antiandrogens which, to date, would appear to be slightly less efficient than castration. They may, however, be of value when cancer cells apparently become hormonoindependent.
It has not been clearly demonstrated that total androgen blockade (castration in association with antiandrogen) is more effective than castration alone. Similarly, trials have been carried out involving intermittent castration in an attempt to resensitise hormono-independent clones. These trials are not particularly conclusive.
Generally, the duration of hormonodependency of metastatic prostate cancer is a longer than one year. However, undifferentiated cancers can be totally resistant from their onset, whereas other cancers may be sensitive for many years.
The treatment is generally well tolerated (despite risk of embolism).
It has been clearly demonstrated that, in order to reduce cancer progression, constant diminution of thyreotrope hormone (TSH) activity is required.
Constant thyroxine treatment is therefore prescribed, with the exception of the iodine brachytherapy period. This irradiation (around 100 mCi of Iodine 131) can be repeated although the tumour gradually becomes dedifferentiated and Iodine is no longer active on the tumour. Radio-induced fibrosis may become toxic (eg. lung metastases and risk of pulmonary insufficiency).
Thyroid hormonotherapy :
Papillary cancer of the thyroid is a lymphophile cancer which accounts for approximately 80% of thyroid cancers. Vesicular cancer, which is rathermore haematophile, represents approximately 15-20% of differentiated thyroid carcinoma.
Both types of cancers capture Iodine.
After radical thyroidectomy (with node sampling), isotopic screening is performed with a tracing dose of Iodine 131. If remaining thyroid tissues are visible on the scintigraphy, an ablative dose of 100 mCi of Iodine 131 is administered in order to deliver selective interstitial brachytherapy on this persistent thyroid tissue.
This treatment should be administered in a specialised hospital room with lead walls, specific toilets to collect contaminated urine and faeces and with particular precautions for dealing with underwear. Nursing and cleaning personnel should be protected by a dosimeter and elementary measures like remaining at a distance from the patient.
If the initial isotopic screening is positive, further screening will be carried out approximately 6 months later. Substitutive hormone therapy should be interrupted in order to obtain correct fixation on the thyroid tissue situated either around the neck or at remote metastases.
In the course of this ablative treatment, constant reducing hormonotherapy should administered with two main goals:
As a substitutive treatment, T4 levothyroxine is the most frequently prescribed hormonotherapy at a dosage of 2-3 µg/kg/d or a mixture of T4 and T3 in order to correct the onset of hypothyroidism.
It is known, for example, since the end of nineteenth century, that bilateral ovariectomy improves breast cancer.
In 1941, Higgins demonstrated that bilateral castration considerably improved metastatic bone pain in prostate cancer sufferers. It is has also been acknowledged for many years that castrated men never develop prostate carcinoma.
Def: Hormonal therapy is one of the major modalities of medical treatment for cancer, others being cytotoxic chemotherapy and targeted therapy (biotherapeutics). It involves the manipulation of the endocrine system through exogenous administration of specific hormones, particularly steroid hormones, or drugs which inhibit the production or activity of such hormones (hormone antagonists). Because steroid hormones are powerful drivers of gene expression in certain cancer cells, changing the levels or activity of certain hormones can cause certain cancers to cease growing, or even undergo cell death. Surgical removal of endocrine organs, such as orchiectomy and oophorectomy can also be employed as a form of hormonal therapy.
In practice, we can study the following cancers as hormonodependent:
- breast cancer,
- prostate cancer,
- corpus uteri cancer,
- thyroid cancer,
- for few and short responses: ovarian and kidney cancers.
content:
Protein receptors to hormones
Role of castration
Role of steroid hormone
Role of analogues of hypothalamic hormones ( LH-RH)
Androgens and anti-androgensEstrogens and anti-estrogens
Progesterone
Anti-aromatase
Adjuvant Hormonotherapy
Hormonal treatment of metastases
Thyroid Hormonotherapy
Hormone receptors :
Steroid hormones (from vitamin D to suprarenal hormones) act by their fixation to a specific receptor situated inside the cell nucleus. The complex is a DNA transcription factor which induces various protein syntheses. Steroid receptors are proteins from 427 to 984 amino acids with many analogical zones from one species to another and from one receptor type to another.
 | General diagram of the action of steroid hormones on hormone sensitive cancer cells The steroids, linked to more or less specific serum proteins, freely penetrate into the cancer cells and are then transported towards the nucleus by a specific cytosol receptor. The receptor itself is bound to the heat shock protein. When in the nucleus, the receptor activates the transcription of the synthesis necessary for good cell trophicity. . |
- Specific hormone recognition domain,
- DNA Binding domain
Assay methods for receptors
Two techniques are used:- Either isotope techniques, using a tracing dose of radioactive hormone, which tests the nuclear extracts
- Or immunochemical techniques which can be applied on tissue extracts or directly on histological preparations.
 |
Relationship between the presence of receptors and survival in breast cancer. |
The presence of receptors is a good prognostic factor: breast cancer patients with positive receptors have a longer survival without relapse than patients without detectable receptors.
There has been less study on receptors for prostate cancer. The conversion of testosterone by the prostate cell via a 5- α reductase, enables the reduced hormonal molecule to penetrate into the nucleus.
Hormonal therapy is based on the possibilities of breaking the interaction between testosterone or its derivative with its receptors, thus reducing the transcription factors induced by the combination of the hormone and its receptor.
Mechanisms of action :
The mechanisms of action of the various hormonal treatments correspond to one of the following:
Disappearance of the stimulating hormone,
Action of an antihormone acting of the receptor,
Inhibition of the synthesis of the stimulating hormone or of its active derivate.
 | The three main mechanisms of hormonal action for prostate cancer:
|
The following pages describe the actions of the various products (or techniques) used in daily clinical practice.
Castration :
In breast carcinoma
Physical castration is generally delivered by radiotherapy or more rarely by coelioscopy. Nowadays, it is performed to a lesser extent in breast carcinoma, mainly due to the simplicity of use of antioestrogen drugs.However, it still constitutes an excellent treatment modality for breast cancer bone metastases (if no previous treatment with antioestrogens has been administered): a very powerful and rapid analgesic effect is generally obtained with tumour regression and often prolonged survival.
There are major side effects among young non-menopaused women, due to the abrupt menopause induced by castration and its often severe psychological consequences.
In prostate cancer
In prostate cancer, castration has a very strong positive effect on local relapse (disappearance of most urinating difficulties) as well as distant bone metastases (very early pains sedation).
Adding castration to local treatment does not appear to be of any value (despite a recent trial demonstrating benefit with an association of radiotherapy and hormonal therapy for large T3 prostate cancer).
 | Diagram of the action of castration on prostate cancer. |
Castration of men is a very simple surgical procedure which can be performed with virtually no hospitalisation and without any major surgical risk. Its cost is very low compared to other treatments proposed further on.
Many of side effects of castration are similar in male and female patients alike. The sudden hormonal deprivation leads to very severe hot flushes, more or less severe hypogonadism (small penis, disappearance of male body hair, softening of the skin, as well as frequent loss of libido with more or less complete impotence (which may already exist in prostate cancer).
There are also many psychological effects: many patients consider castration as an attack on their integrity (many physicians are reluctant to propose such ‘mutilation’ and prefer ‘chemical castration’ which, during the first months at least, appears less aggressive.
Pulpectomy is another possible method, consisting in the removal of the testicular parenchyma whilst conserving the testicular capsule, thus giving a false impression of organ conservation. Some surgeons also suggest replacing testes by prostheses.
Steroid hormones :
In breast carcinoma
Androgens were previously used for treating metastatic breast carcinoma.They induce a castration effect by blocking hypothalamus hormones.
The virilisation observed in long_term treatment, together with the risks of hypertension and the appearance of new drugs, far better tolerated by patients, have led to the disappearance of androgens from the therapeutical repertoire, except (perhaps) in pre-terminal phases when their anabolising effect can be useful (improved appetite, lesser asthenia).
In prostate cancer
Oestrogens were, for a long time, used to treat prostate cancer.The most frequently used drugs were diethylstilbestrol as well as estradiol di-undecylate (or Oestradiol –Depot ).
They have peripheral side effects which are symptoms of feminisation: gynaecomastia, altered repartition of fatty tissue), however their main action consists in blocking the secretion of the hypothalamus hormone LH RH, thus inducing a suppression of LH by the pituitary gland and secondarily of testosterone by the testis.
 | Mechanisms of action of oestrogens for prostate cancer |
Oestrogens (especially at high prolonged dosages 3mg/d) have been abandoned because of the thrombosis and embolism complications that they induce and which diminish the positive effect of the treatment in randomised studies. Unfortunately, a dosage of 1 mg/d may not be sufficient for all patients. Thus, (at least in France), oestrogens are no longer a first-line hormonal treatment for prostate cancer.
Following the failure of first-line hormonal treatment, DES may offer significant responses.
Oestrogens can also be used in a loading dose (for acute complications which are not amenable to surgery or radiotherapy, such as diffuse medullar compression or very intense pain).
Fosfetrol (or ST 52) is a prodrug which brings the active agent to the prostate. Dephosphorylation induces the formation of the active metabolite: diethylstilbestrol (DES). Due to the presence of acid phosphatases, Fosfetrol is mainly (but not solely) transformed at the tumour site, which avoids general oestrogen treatment and a much higher dosage to the prostate, thus limiting the risk of gynaecomastia, thrombosis and pulmonary embolism.
Moreover, as for oestrogens, the inhibition of the hypothalamus-pituitary axis is observed, thus reducing the testicular synthesis of androgens.
Agonists of LH-RH :
The synthesis of numerous LHRH analogues and the production of easy to use galenic forms (injections with depot properties) has transformed the hormonotherapy of prostate cancer (and to a lesser extent breast cancer)
These drugs have many non-cancer-related indications (endometriosis, uterine fibroma, ovarian polycystosis, hirsutism).
The main drugs are:
The mechanism of action of these LHRH agonists is explained by the down-regulation in the pituitary gland: pituitary receptors for LHRH are totally saturated and then down-regulated with loss of sensitivity to any further stimuli. The gonad receptors for LH and FSH are then reduced. High dosage of LHRH agonists induces inhibition of pituitary and gonad functions (sex steroid deprivation).
- buserelin,
- goserelin,
- leuprorelin,
- triptorelin.
The pituitary cells, will initially respond to the stimulation of hypothalamic hormone analogues by increased LHRH secretion. The testis will respond to this secretion by increased testosterone synthesis.
 | Action of the agonists of LH RH: first step |
Treatment by LHRH agonists should therefore not be initiated without previous antiandrogen treatment (or antioestrogen for breast cancer) over a few days.
It is quite possible that these agonists have a direct action on tumour cells, since rare observations of responses in castrated men (or women) have been described.
The secondary effect of agonists involves chemical castration by the exhaustion of the pituitary gland. Hot flushes are frequently observed and castration leads to impotence (in almost all patients), loss of libido and major hypogonadism.
 | Treatment by agonist of LH-RH : second step. |
In prostate cancer, up to 70% of remissions are obtained using this treatment and their mean duration is around one to three years (and much longer among certain patients).
In breast cancer, this treatment is often instituted in order to obtain non-definitive castration for young patients in the hope of a return of normal menstruation.
Antiandrogens :
Antiandrogens are very powerful drugs which act on the androgen receptor and are used to treat metastatic prostate carcinoma.
We can distinguish two categories of anti-androgens:
Progestative drugs
They are represented by cyproterone acetate. They possess a double effect:- by their action on the hypothalamus, they down-regulate the secretion of androgens by the testis (castration),
- by their effect on the androgen receptor of the tumour cells, they block the development of this hormone-dependant cells.
 |
| Mechanisms of action of cyproterone |
The side effects of this product are either related to hormonal deficiency (loss of libido, impotence, asthenia, moderate gynaecomastia) or to vascular disorders (venous thrombosis) or, more rarely, liver toxicity (cytolysis).
Nonsteroidal antiandrogens
These antiandrogens inhibit the translocation of protein cytoplasmic receptors towards the nucleus after fixation to the hormone.There is no testosterone concentration diminution: thus no hot flushes, no or limited loss of libido and a variable diminution of sexual potency.
 |
| Mechanisms of action of nonsteroidal antiandrogens |
A relatively high number of molecules are available:
- nilutamide,
- bicalutamide,
- flutamide.
Progestative drugs :
The presence of progesterone receptors in breast cancer cells and in endometrial cancer cells has led to the use of progestative drugs for advanced or metastatic cancer.
In metastatic corpus uteri cancer (more than 80% of patients are cured with local treatment), progestative drugs give a response rate of around 30% for patients with a progesterone receptor and less than 10% for others. This treatment is generally very well tolerated, hence its prescription in all palliative situations before chemotherapy, which is not very efficient.
In breast carcinoma, the progestative molecules (such as megestrol acetate) are prescribed as second-line hormonotherapy: their efficiency is proportional to the efficiency of first–line hormonotherapy (generally tamoxifen).
Progesterone also has a positive effect on appetite and general status (as for cortisone and androgens) but it can induce hydric retention.
Progesterone dosage for this indication is rather high. The following drugs are available:
- medroxyprogesterone,
- megestrol.
Aminoglutethimide :
Aromatase is an enzyme which catalyses three hydroxylations which are necessary for the metabolism of steroidal hormones from cholesterol. It is present in great quantities in the adrenal gland and ovaries, and most probably in other tissues (present in mammary cells).
Aminoglutethimide acts in the same manner as chemical adrenalectomy, i.e. blocks the synthesis of minor androgens and oestrogens by the adrenal gland. It also disturbs the synthesis of hydrocortisone, thus, in order to avoid Addison’s disease, small doses of hydrocortisone should be simultaneously administered.
 |
| Blockade of synthesis by aminoglutethimide |
 |
| Diagram of the action of a classical antiaromatase on prostate cancer: aminoglutethimide |
Antiaromatase drugs :
Ovarian aromatase plays the same major role as adrenal aromatase in oestrogen synthesis.
The ovary, as an endocrine gland, can be considered as having two compartments: the interstitial or stromal compartment which is under the influence of LH, controls the synthesis of androstene dione by stroma cells. In the thecal compartment, granulosa cells, under the influence of FSH, regulate the quantity of aromatase in order to synthesise oestrone and oestradiol. The level of aromatase at ovulation is 8 to 10 times higher than during menstruation.
 | Role of ovarian aromatase |
 |
Action of anti-aromatase drugs |
New synthetic antiaromatase drugs are currently manufactured: they act by direct competition with the enzyme (derived from imidazole) and directly prevent the transformation of androgens into oestrogens (particularly inside tumour cells).
 | The association of aromatase (which combines with androgen (or Target) and a co-enzyme (reductase). Together they synthesise Oestrogen. |
type I antiaromatases, of steroid origin: they irreversibly bind to the enzyme action site (suicide inhibitors). In order to synthesise oestrogens from androgens, the cancer cells must also synthesise aromatase.
type II antiaromatases act on cytochrom P450 reductase; the co-enzyme of the enzymatic complex necessary for aromatase activity, and block it in a reversible and transitory manner:
- formestane,
- anastrozole,
 | The two types of antiaromatases: type I: competition with androgen (target) in an irreversible link type II: action on the coenzyme: cytochrom P 450 reductase |
In breast cancer, antiaromatases are very efficient with at least a 35% response rate as first-line hormonotherapy among metastatic patients.
The comparison between anastrozole or letrozole with tamoxifen reveals a similar efficiency against cancer cells, however the toxicity profile is lower with no risk of thrombosis or embolism, and no risk of secondary endometrial cancer. Osteoporosis is an added complication which has not yet been completely evaluated. Thus, for many oncologists, antiaromatases are an interesting alternative to antioestrogens.
Adjuvant hormonotherapy :
In breast carcinoma
Despite some side effects, it has been clearly demonstrated that tamoxifen prescribed as an adjuvant treatment offers major benefit for patients with positive oestrogen receptors, independently of age.This was clearly demonstrated by meta-analysis carried out it 1988 which revealed patient benefit independently of node status. The decreased risk of relapse was more significant during the first 5 years than during the following 5 years. However, a decrease in death rate was also systematically observed.
Consensus conferences by the NIH recommend the prescription of antioestrogens for all women with positive receptors, without taking into account tumour size or node status.
There is also a ±50% decrease in the risk of second breast cancer (controlateral) during the first five years, even when the tumour does not bear receptors.
The prolonged and systematic prescription of tamoxifen is limited by the increased risk of corpus uteri cancer (despite the fact that it is very often a minor and surgically curable cancer).
In the future, antiaromatase drugs may have an equivalent role in this adjuvant setting (but at a much higher cost), but our experience is, as yet, insufficient for us to be totally certain of this role. We are unaware of the exact incidence and gravity of potentially induced osteoporosis.
Ovarian suppression (for non-menopaused women), in an adjuvant setting, would also appear to be beneficial (reduction in relapse of 13%) and a probable increase in survival Although most meta-analyses have been developed with surgical or radiotherapic castration, it seems logical that ovarian suppression induced by LHRH agonists will offer the same benefits. These drugs have the advantage of enabling non-definitive castration, which is a very important point for young women who may desire pregnancy at distance from their cancer treatment.
In prostate carcinoma
Adjuvant therapy does not appear to bring any benefits in localised disease either before or after radical prostatectomy. Such treatment does not reduce the number of positive margins and does not increase disease-free survival.In locally advanced disease (T3 with elevated Gleason histological grade or high levels of PSA), Bolla demonstrated a clear advantage in the simultaneous association of radiotherapy and hormonotherapy which should be prescribed for at least 3 years. There is no data for smaller stages.
For these patients, hormonotherapy carries an impotence risk close to 100%, whereas sexual potency (possibly with the help of Viagra) may resist radiotherapy.
Hormonotherapy for metastases :
In breast cancer
Hormonotherapy is the leading treatment for metastatic breast cancer among post-menopausal women. It offers significant increase in survival and quality of life. Most patients with positive receptors on primitive tumours will respond positively to hormonotherapy when metastases occur. Even among patients with negative receptors, an attempt at short hormonotherapy is possible (particularly for elderly patients), since certain metastatic tumours may response, despite the fact that the primitive tumour had no receptors (tumour variability).Hormonotherapy is generally well tolerated. Treatment should begin with tamoxifen or an antiaromatase drug. The effect is produced within a few days or a few weeks. Hormonotherapy may be associated with other specific treatment modalities such as bone radiotherapy or surgery. Patients relapsing after tamoxifen may still obtain a good response with an aromatase inhibitor.
For pre-menopausal women, tamoxifen offers more or less the same efficiency as castration: the response duration (which is not, unfortunately, constant) is generally greater than one year, but can be much longer. For young patients, castration is performed at relapse. Antiaromatase drugs are not particularly efficient due to their high level of ovarian oestrogens (except after castration). The general use of chemotherapy, with its high response rate, sometimes clouds the value of hormonotherapy in terms of patient comfort.
Bone metastases are often very sensitive to hormonotherapy (pain reduction) although it may be difficult to establish the objective responses.
When metastases develop under hormonotherapy, it should be concluded that the tumour is hormonoindependent and chemotherapy should be attempted.
In prostate cancer
When metastases occur, hormonotherapy is the leading treatment.Surgical castration is the easiest and less expensive treatment. However, psychologically, it is often very poorly tolerated. However, its effect, (particularly for painful bone metastases) can be quite spectacular with patients experiencing no pain as early as the day after surgery. Of course, the androgenic deprivation cannot correct mechanical disorders (such as medullar compression or pre-fracture syndrome for which a surgical solution may be sought).
LHRH agonists (after a short period of antiandrogen treatment) is now the preferred chemical castration method, in a more expansive and elegant manner. Treatment should be pursued without interruption, even when the tumour becomes hormono-independent, otherwise hormone-dependent clones may reoccur. The side effects of surgical and chemical castration are identical.
Oestrogens are rarely prescribed (in correlation with their cardiovascular toxicity). They can, however, be useful if an acute metastasis occurs (with associated local treatment if necessary).
Many trials are underway in order to precisely define the role of antiandrogens which, to date, would appear to be slightly less efficient than castration. They may, however, be of value when cancer cells apparently become hormonoindependent.
It has not been clearly demonstrated that total androgen blockade (castration in association with antiandrogen) is more effective than castration alone. Similarly, trials have been carried out involving intermittent castration in an attempt to resensitise hormono-independent clones. These trials are not particularly conclusive.
Generally, the duration of hormonodependency of metastatic prostate cancer is a longer than one year. However, undifferentiated cancers can be totally resistant from their onset, whereas other cancers may be sensitive for many years.
In corpus uteri cancer
Progesterone is prescribed for metastatic cancer, which concerns approximately 20% of patients. The response rate with progesterone is around 30%, a few patients benefiting from very long remission. It is inefficient as an adjuvant treatment.The treatment is generally well tolerated (despite risk of embolism).
In metastatic thyroid carcinoma
Radioactive iodine treatment allows metastasis-specific interstitial radiotherapy (or brachytherapy).It has been clearly demonstrated that, in order to reduce cancer progression, constant diminution of thyreotrope hormone (TSH) activity is required.
Constant thyroxine treatment is therefore prescribed, with the exception of the iodine brachytherapy period. This irradiation (around 100 mCi of Iodine 131) can be repeated although the tumour gradually becomes dedifferentiated and Iodine is no longer active on the tumour. Radio-induced fibrosis may become toxic (eg. lung metastases and risk of pulmonary insufficiency).
Thyroid hormonotherapy :
Papillary cancer of the thyroid is a lymphophile cancer which accounts for approximately 80% of thyroid cancers. Vesicular cancer, which is rathermore haematophile, represents approximately 15-20% of differentiated thyroid carcinoma.
Both types of cancers capture Iodine.
After radical thyroidectomy (with node sampling), isotopic screening is performed with a tracing dose of Iodine 131. If remaining thyroid tissues are visible on the scintigraphy, an ablative dose of 100 mCi of Iodine 131 is administered in order to deliver selective interstitial brachytherapy on this persistent thyroid tissue.
This treatment should be administered in a specialised hospital room with lead walls, specific toilets to collect contaminated urine and faeces and with particular precautions for dealing with underwear. Nursing and cleaning personnel should be protected by a dosimeter and elementary measures like remaining at a distance from the patient.
If the initial isotopic screening is positive, further screening will be carried out approximately 6 months later. Substitutive hormone therapy should be interrupted in order to obtain correct fixation on the thyroid tissue situated either around the neck or at remote metastases.
In the course of this ablative treatment, constant reducing hormonotherapy should administered with two main goals:
To avoid hypothyroidism, which is very rapidly poorly tolerated by patients,
The TSH level should be lower than 0.02 mU/l. Thyroglobulin level should also be controlled.To block the TSH axis thus avoiding the development of metastases.
As a substitutive treatment, T4 levothyroxine is the most frequently prescribed hormonotherapy at a dosage of 2-3 µg/kg/d or a mixture of T4 and T3 in order to correct the onset of hypothyroidism.
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