Chimiotherapie

Prostate cancer at high risk – When and on what criteria chemotherapy should be considered?

About 71,000 new cases annually of prostate cancers in France, 10,000 are considered high risk, that is to say, likely to develop metastases and spread to adjacent organs.

Therapeutic solutions comprise a succession of treatments, each of which is introduced as soon as the failure of the previous proven. Instead of chemotherapy typically intervene as a last resort, because of their reduced impact on the useful lives and their heavy side effects.

The proposed new molecules could be prescribed earlier or in combination with other treatments.

 

The treatments offered chemotherapy before use

Surgery or radiotherapy concomitant hormone protocol are indicated as first-line treatment when a curative is possible. Interstitial brachytherapy, the focused ultrasound, or cryotherapy is not indicated in these aggressive forms at high risk.

Palliative treatments involved the incurable stage of the disease, to improve the quality of life of patients without prolonging survival.

Hormonal treatments are then prescribed in first intention.

Signaling Effects of hormones on CA

The principle of hormone-dependent prostate cancer was established by the historical works of Charles HUGGINS(published in 1941) showing that surgical castration (bilateral orchiectomy) has a favorable effect on the metastatic cancer developments prostate. The direct consequence of orchiectomy is a radical lowering of testosterone to very low residual values. Without testosterone, tumor cells atrophy, is vacuolisent and die, bone metastases regress within three months.

L’axe hypothalamus - hypophyse - testicule

 

These hormonal therapies are indicated when there are uncomfortable symptoms impair patients’ quality of life:

  • micturition disorders and / or bloody urine (haematuria) in relation to the invasion by cancer of the urethra or prostate of the floor of the bladder,
  • bone pain related to the dissemination of bone metastases.

Androgen deprivation can be performed by surgical castration orchidectomy, bilateral or pulpectomy which keeps the envelope of the testis removes the pulp which secretes hormones. This procedure is rarely performed nowadays.

Neutering is usually chemical effect, achieved with drugs:

  • The first generation anti-androgens block androgen receptors to cells of the body including those of the prostate. Some anti androgens have a peripherally acting as Nilutamide (Anandron ®) or Bicalutamide (Casodex ®). Others centrally and peripherally acting as cyproterone acetate (Androcur ®). These treatments are administered orally;
  • The LHRH agonists (Luteinizing Hormone Releasing Hormone, also called GnRH = gonadotropin-releasing hormone) result in suppression of serum testosterone effect of depletion of LHRH receptors. Their effectiveness is considered equivalent to surgical castration; therefore they have now become the main form of hormone therapy because of their reversible action and therefore less traumatic for patients that surgical castration. The molecules used are Triptoreline (Decapeptyl ®), Leuprorelin (Enantone Eligard ® or ®) and acetate Goserelin (Zoladex ®). These treatments are administered quarterly or half yearly injections;
  • The LHRH antagonists also block axis hypothalamus – hypophysis – Testis, thereby abolishing the secretion of testosterone by the testis. This is the degarelix (Firmagon®) administered monthly injections;
  • Female hormones, estrogens such as diethylstilbestrol (Distilbène ®), which have long been the standard treatment, are rarely used today as a first line in this indication antagonizing male hormones. They pose significant risks to the patient of thromboembolic complications, sometimes fatal (phlebitis, pulmonary embolism).
Sites d’action de l’hormonothérapie des cancers de prostate

External beam radiation therapy also has a place to palliation, for example to irradiate painful bone metastases. This is a focal treatment which can not act on all the areas disseminations metastasis.

The efficiency of hormonal treatments is limited in duration. After a variable period of time, two years on average, patients are often required to develop hormone resistance: it is the exhaust to hormonal treatment favored by changes in the expression and structure of genes that allow the emergence and development of new clones of cancer cells resistant to hormonal therapy.

Other hormonal treatments second line can then be administered to improve the quality of life of patients.

These new molecules antiandrogens whose leader is abiraterone acetate (ZYTIGA®). These new molecule antagonists of the androgen receptor, and even the very recent as MDV3100 (enzalutamide) or RD162, struggling against the intratumoral activation of androgens. Their effectiveness has been confirmed and they are used just after the onset of hormone resistance or after failure of first-line chemotherapy with cytotoxic molecules.

Place of chemotherapy in treatment strategies

No first-line use

Chemotherapies act against all cancer cells, even those not detected by imaging, but they do, however, represent a first line treatment. Indeed, the former proposed molecules have limited effect: they operate only during cell division, and their action is therefore limited to the rapidly dividing cells as prostate cancer progresses slowly.

Thus, they remain little used and limited to pain relief because they do not lead to obvious improvements while generating heavy side effects.

These are quite well known: nausea and vomiting, hair loss, infertility, great fatigue, skin problems, …

Current indications chemotherapy

Currently, chemotherapy generally remains the reference treatment in case of castration resistance (when the decline in testosterone is no longer possible to stop the appearance of metastases) or to other treatments described above, as well as if severe pain.

It temporarily blocks the progression of the disease and its dissemination by acting on resistant cancer cells and decreasing the spread of cancer and the pain it causes, without cure. For patients resistant to hormonal castration, the European Association of Urology and recommends its immediate use as soon as the occurrence of raw pain.

Place of new chemotherapies

– The new chemotherapies of prostate cancer involve cytotoxic molecules to targeted therapies represented by inhibitors of tyrosine kinases and anti-angiogenic, or to novel immunotherapies and Denosumab.

– The leader of cytotoxic molecule is Docetaxel (Taxotere®). Combined with Prednisone ® (corticosteroid) or estramustine (Estracyt ® = estrogen derivative), it extends the life of several months and reduce patient suffering. These cytotoxic molecules are indicated as a treatment for metastatic prostate cancer and SYMPTOMATIC resistant to castration, and in case of visceral metastases.

– In case of failure of docetaxel, cytotoxic chemotherapy for second-line call at Cabazitaxel (Jevtana ®) or Mitoxantrone (Novantrone ®).

The pace of treatments and dosages are based on the types of cancer, health status and patient decisions and their tolerance to these treatments.

– Targeted therapies are tested in monotherapy or in combination with cytotoxic. The molecules used are:

  • tyrosine kinase inhibitors such as Sorafenib (Nexavar ®)
  • or sunitinib (Sutent ®) antiangiogenic as Bevacizumab (Avastin ®)

– Immunotherapies as Sipuleucel T (Provenge ®) are true vaccines used in the context of prostate cancer. They are indicated in cases of metastatic prostate ASYMPTOMATIC castration resistant.

– All patients with bone metastases, prevention of skeletal events (pathological fractures, spinal cord compression or when radiation or surgery to bone) is a priority treatment. She called bisphosphonates like zoledronic acid (Zometa ®) or Denosumab (Xgeva ®).

Currently only 10% of French patients have recourse to chemotherapy, but if the benefits of new molecules were confirmed statistically, they could be used in conjunction with surgery, or directly in the case of metastases. Moreover, chemotherapy may be recommended as first choice in patients at risk of rapid development of new metastases or severe pain.

Some bibliographical elements

Hormonal therapies

http://www.cancer.ca/fr-ca/cancer-information/diagnosis-and-treatment/chemotherapy-and-other-drug-therapies/hormonal-therapy/?region=on

Therapeutic strategies in case of resistance to hormonal castration

http://urofrance.org/fileadmin/medias/congres-francais-urologie/2010/dossier-presse-traitements-cancer-prostate.pdf

http://urofrance.org/fileadmin/documents/data/PU/2011/v21sS2/S116670871170015X/main.pdf

Chemotherapy side effects

http://www.prostatecancer.ca/Prostate-Cancer/Treatment/Chemotherapy?lang=fr-CA#.VUZ7OPntmkp

Place of chemotherapy in therapeutic strategies

http://urofrance.org/science-et-recherche/base-bibliographique/article/html/place-actuelle-de-la-chimiotherapie-dans-le-traitement-du-cancer-de-la-prostate-metastatique-hormo.html

Future treatments

http://www.ourvoiceinprostatehealth.com/fr/articles/2010/10/de-l%E2%80%99espoir-%C3%A0-l%E2%80%99horizon

http://www.current-oncology.com/pages/files/FULL%20final%20french%20reduced%20for%20website.pdf