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Drug therapy of prostate cancer

Multiple types of drug therapies are used to treat prostate cancer at different disease stages.  

  • Endocrine therapy
  • Chemotherapy
  • Bisphosphonates and RANK ligand inhibitors
  • Androgen synthesis inhibitors
  • Other drugs

Hormone manipulation

Hormone manipulation is used when tumor spreading has been confirmed, or the tumor has advanced locally and is not a candidate for curative treatment. This type of treatment may extend life, retard tumor growth rate, and reduce the amount of cancer cells in many patients.

Hormone manipulation can also be given along with comprehensive curative radiation therapy to the prostate gland (radical radiation therapy). This is done when there is no detected spreading, and will improve the prognosis for patients receiving radical radiation therapy in high or intermediary risk groups.

Hormone manipulation for advanced disease can increase quality of life and relieve symptoms, however the treatment may also cause side effects and reduce quality of life. In these situations, balance is the goal in terms of choice of treatment regimen and when treatment is initiated. 

The two main hormone manipulation alternatives used are:  

  • Antiandrogens
  • Testosterone deprivation (chemical or surgical castration) 

Antiandrogen therapy 

Antiandrogen therapy is primarily for patients with locally advanced disease without confirmed spreading and who are not candidates for radical surgery or radiation therapy, with spreading to lymph nodes.  In the event of bone or other metastasis, testosterone blocking treatment is standard. Use of antiandrogen therapy for limited spreading to bone is considered for certain patients without ordinary indication.

Treatment with antiandrogens is not castration. Antiandrogens block testosterone chemically to avoid stimulation of prostate cancer cells. Testosterone production is still maintained and the patient avoids to a great extent the side effects of castration.

There are two main relevant side effects requiring action: 

  • Soreness in the breasts and/or enlargement of breasts. This is prevented in most patients by short-term radiation therapy to the breasts at the start of treatment. If the breasts are not irradiated at the start of treatment, it is not possible to reverse enlargement with radiation therapy later. Surgery will then be necessary.  
  • Liver function values must be checked at treatment start and at regular intervals, since liver function is influenced by treatment with these drugs. 

There are essentially two types of antiandrogens used in the treatment of prostate cancer today, either steroid antiandrogens or non-steroidal antiandrogens. The most important non-steroidal antiandrogens are bicalutamid and flutamid.

Bicalutamid is taken once daily. Flutamid is taken 3 times daily, however this drug is rarely used. 

 

Testosterone deprivation treatment

Stop of testosterone production (castration) is done by: 

  • surgical removal of both testicles (immediate stop of testosterone production) 
  • chemical castration by addition of LHRH analogues or LHRH antagonists

The side effects of this treatment are hot flashes, reduced/elevated libido with subsequent erectile dysfunction, fatigue, muscle weakness, joint pain, depression and mood swings. These side effects are due to lack of testosterone. Surgical and chemical castration usually have an equivalent effect on the disease, and largely have the same side effect profiles. The side effects of castration treatment may be different, partially depending on the age of the patient. For younger men, the influence on sexual function may be the most frightening. The majority of patients lose interest for sexual activity over time. After many years of testoterone deprivation, the patient may develop osteoporosis and have an increased risk for diabetes and heart disease.

LHRH therapy

Chemical castration with “Lutinizing Hormone Releasing Hormone” analogues (LHRH) leads to a temporary increase of serum testosterone with a risk of a transient worsening of the disease for 2-3 weeks. The LHRH-treatment should therefore always be combined with antiandrogens the first months. The advantage of LHRH is first and foremost that if discontinued within 1-2 years, the testicles will resume testosterone production (castration treatment is reversible).  So-called “intermittent androgen suppression” may be appropriate for some patients.

LHRH antagonists (degarelix) provide the same reduction in testosterone, but without the transient initial increase. These patients do not need antiandrogens if the disease is extensive at the start of treatment. 

Combination of LHRH-analogues and antiandrogens (total androgen blockade) 

In some cases, antiandrogen and LHRH treatments are combined. However, it is not confirmed whether this treatment improves survival.

Estrogen therapy 

With production of female sex hormones, testosterone production is reduced with a similar effect on the development of prostate cancer as for LHRH analogues or LHRH-antagonists. The relevant drug is polyestradiolphosphate. In addition to the possible beneficial effect, estrogen treatment may to some extent increase the risk thrombo-embolic events and heart disease. Estrogen therapy is currently not widely used for these patients. An advantage of this drug is that it causes few hot flashes.

Chemotherapy

In the event of progression after castration treatment (surgical or chemical), chemotherapy is the standard treatment today for suitable patients. Treatment can often be given to patients in their upper eighties with a function level of 0-2.

In randomized studies, docetaxel has been shown to increase survival in hormone refractory, metastasizing disease. The effect appears to be optimal in a regimen where docetaxel is given once every third week. Risk of osteoporosis with increased risk of infection may however be less with weekly administration in 5 or 6 subsequent weeks. This should be considered if the patient is 75-80 years.

Data became available in 2010 for second line chemotherapy with cabazitaxel giving extended survival after treatment with docetaxel. Cabazitaxel is approved and used in Norway. The risk for osteoporosis with neutropenia with threat of serious infections is greater with this treatment than with docetaxel. The number of suitable patients for this treatment is drastically less than for docetaxel. The general tolerance for this drug is relatively good, and it seems the risk for bothersome paresthesia is less. 

Bisphosphonates and RANK ligand inhibitors

Zoledronic acid and denosumab have documented effects on pain and bone-related symptoms on castration-resistant disease with bone metastases. This treatment is given intravenously or subcutaneously every 4 weeks and is combined with calcium and vitamin D supplements. Survival is not prolonged with this treatment, and there are no data to confirm optimal treatment duration.

Among the side effects are transient reduction of general health (especially after first treatment), fever, skin rash, and osteonecrosis of the jawbone. It is critical that patients are examined by a dentist before starting this treatment, and that extractions or other dental work that may influence the jawbone is avoided after treatment is initiated, unless absolutely necessary. The dentist should then consult with the maxillofacial surgeon. Treatment with zoledronic acid requires regular monitoring of liver function. 

Androgen synthesis inhibitors

Abiraterone is an androgen synthesis inhibitor, which affects the production of cancer cells in the adrenal glands and cancer cells of hormones that resemble testosterone stimulating growth of prostate cancer cells. It has been shown in a randomized study that treatment with this drug extends survival after previous treatment with docetaxel. There are also positive results with treatment of abiraterone given before chemotherapy, but due to crossover it is less certain what the survival gain is in these patients. Side effects are very mild (less side effects were reported in the treated arm than the placebo arm). 

Abiraterone is given with steroids, normally prednisolone 5 mg x 2 due to the risk for suppression of adrenal steroid production. This drug is now approved for use both before and after chemotherapy and for castration-resistant patients with metastases.

Other drugs

There are multiple other drugs showing promising results which are either under approval by drug authorities in the EU and Norway, or are in final research phases. They are not routinely available. Among these are enzalutamide and alpharadin. These drugs have been shown to extend survival in phase III studies. These are available for certain programs/protocols, but they are often time-limited and availability changes erratically.  

Drugs under investigation

There will always be drugs under investigation around the world, also in Norway in periods. It is important to keep in mind that a drug under investigation may have no documented effect and cannot/should not be used without a protocol. There are examples where use of drugs under investigation have produced the opposite effect - shortening survival or quality of life for patients.

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