PROSTATE CANCER TREATMENT ? Op. Dr. Ali G?RTUNA | Sa?l?k

---

Prostate cancer treatment: hormone therapy I
Metastatic disease is the cause of nearly all prostate cancer-related death. Currently incurable, 5-year survival is 25%; 10% survive <6 months, while <10% survive >10 years. The mainstay of treatment is hormone therapy, with cytotoxic chemotherapy in reserve and novel treatments such as growth factor inhibitors, angiogenesis inhibitors, immunotherapy, and gene therapy in development. The concept of hormone therapy was realized in 1941 when Huggins and Hodges reported favourable acid and alkaline phosphatase responses in prostate cancer patients castrated or given oestrogens.

Hormone dependence of prostate cancer treatment
95% of circulating androgen, mainly testosterone, is produced by the Leydig cells of the testes under the influence of luteinizing hormone (LH). The anterior pituitary synthesises LH, stimulated by LH-releasing hormone (LH-RH) produced by the hypothalamus. The remaining 5% of circulating androgen is synthesized by the adrenal cortex from cholesterol, under the influence of pituitary ACTH. Testosterone is metabolized to the more potent dihydrotestosterone (DHT), by types 1 and 2 5-? reductase (5AR) enzymes. DHT binds to the androgen receptor, travels to the cell nucleus, and exerts its positive effect on cell growth and division. All prostate epithelial cells are dependent on androgens and fail to grow or undergo programmed cell death in their absence. Similarly, most previously untreated prostate cancer cells are dependent on androgens.

Androgen deprivation results in a reduction in PSA and clinical improvement in >70% of patients. However, most will still die within 5 years due to the development of androgen-independent growth. This is considered to be due to growth of androgen-independent cell clones rather than a de-differentiation of previously androgen-dependent cells. The mean time to disease progression after androgen deprivation is 14 months in men with metastatic disease.

Prognostic factors
Predictors of poor hormone therapy response include:
- metastatic lesions at presentation
- Elevated alkaline phosphatase at presentation
- Anaemia at presentation
- Poor performance status (level of activity) at presentation
- Low serum testosterone at presentation
- Failure of bone pain to improve within 3 months of treatment
- Failure of PSA to normalize within 6 months of treatment (conversely a PSA nadir (= lowest value) of <0.1ng/ml predicts a long-term response)

prostate cancer treatment : hormone therapy II
Mechanisms of androgen deprivation
- Surgical castration: bilateral orchidectomy
- Medical castration: luteinizing hormone-releasing hormone (LH-RH) agonists, oestrogens; also termed androgen ablation or androgen deprivation
- Anti-androgens (steroidal or non-steroidal): androgen receptor blockade at target cell
- Maximal androgen blockade (MAB): medical or surgical castration plus anti-androgen
- 5?? reductase inhibition (5ARI) with finasteride or dutasteride

Both forms of castration have equivalent efficacy, so patients should be given the choice. Oestrogens are no longer used first-line, due to the significant cardiovascular morbidity observed when they were the only alternative to orchidectomy. Anti-androgens alone are less effective in treating metastatic disease, but equivalent for non-metastatic disease. MAB has a theoretical advantage over castration in blocking the effects of the adrenal androgens, but significant clinical advantages have not been demonstrated in trial meta-analyses. 5ARIs are not licenced for the treatment of prostate cancer, but appear to have a role in prevention.

Bilateral orchidectomy ? prostate cancer treatment
A simple procedure, usually carried out under general anaesthesia. Through a midline scrotal incision, both testes may be accessed. The tunica albuginea of each testis is incised and the soft tissue content is removed, after which the capsule is closed. The epidiymes and testicular appendages are preserved. Post-operative complications include scrotal haematoma or infection (both rare). Serum testosterone falls within 8h to <0.2nmol/l.

LH-RH agonists ? prostate cancer treatment
Developed in the 1980s, giving patients an alternative to bilateral orchidectomy, with which they are clinically equivalent. They are given by subcutaneous or intramuscular injection, as monthly or 3-monthly depots. Examples include goserelin, triptorelin, and leuprorelin acetates. If the anterior pituitary is overwhelmed with an analogue of LH-releasing hormone (LH-RH), it switches off LH production, although serum testosterone rises in the first 14 days due to a surge of LH. This can result in? tumour flare , manifest in 20% patients with increased symptoms, including catastrophic spinal cord compression. To prevent this, cover with anti-androgens is recommended for a week before and two weeks after the first dose of LH-RH agonist.
An LH-RH antagonist is in development which should rapidly reduce serum testosterone.

Side-effects of bilateral orchidectomy and LH-RH agonists
- Loss of sexual interest (libido) and ED
- Hot flushes and sweats can be frequent and troublesome during work or social activity
- Weight gain
- Gynaecomastia
- Anaemia
- Cognitive (mood) changes
- Osteoporosis and pathological fracture secondary to osteoporosis may occur in patients on long-term (>5 years) treatment

Anti-androgens ? prostate cancer treatment
These are administered as tablets. Examples include bicalutamide (150mg daily as monotherapy; 50mg daily for MAB, in combination with LH-RH analogues or orchidectomy), flutamide, and cyproterone acetate. The first two raise the serum testosterone slightly, so sexual interest and performance should be maintained, although many such patients have pre-existing ED due to the advancing disease. Side-effects include frequent gynaecomastia, breast tenderness, and occasional liver dysfunction; flutamide also causes frequent GI upset. At its full dose of 100mg tds cyproterone acetate may cause reversible dyspnoea; it may be used at 50mg bd for treatment of castration-induced hot flushes.

Management of advanced prostate cancer: hormone therapy III
Monitoring prostate cancer treatment
Typically, patients will have baseline PSA, full blood count, renal and liver function tests, a renal ultrasound, and a bone scan. The PSA is repeated after 3 months, 6 months, and 6-monthly thereafter until it rises. Liver function is checked 3-monthly if anti-androgen monotherapy is used. Renal function should be checked on disease progression, and bone imaging if clinically indicated.
While PSA is very useful as a marker for response and progression, 15% of patients show clinical progression without PSA rise. This may occur in anaplastic tumours that fail to express PSA.
Advice on exercise, diet, and treatment of erectile dysfunction is often sought by patients during treatment.

Early versus delayed hormone therapy
Traditionally, hormone therapy was reserved for patients with symptomatic metastatic disease. Arguments against early hormone therapy revolve around its side-effects and cost.
However, studies of patients with locally advanced and metastatic disease have demonstrated slower disease progression and reduced morbidity when treated with androgen deprivation early (i.e. before the onset of symptoms). Improved survival has also been reported in patients without bone metastases but including node-positive disease, when treated immediately.
Trials have also demonstrated slower disease progression in patients given bicalutamide 150mg daily (compared with placebo) for 2 years after treatment of high-risk, clinically localized prostate cancer with RP or RT. This benefit is not seen in patients managed by watchful waiting.

Intermittent hormone therapy
The potential advantages of stopping hormone therapy when the disease has remitted, then re-starting it when the PSA has risen again are the reduced side-effects and cost. However, there are no randomized trials yet demonstrating survival equivalence or advantage. None of the LH-RH analogues or anti-androgens are licensed for intermittent therapy. Moreover, it can take up to 6 months after stopping treatment for the serum testosterone to recover, hence side-effects may persist into the off-treatment periods.

prostate cancer treatment: androgen-independent disease
Second-line hormone therapy
When the PSA rises from its lowest (nadir) value, or if symptomatic progression occurs despite a favourable biochemical response to first-line hormone therapy, the disease has entered its androgen-independent phase. In these circumstances, further treatment is usually considered. Most patients receiving anti-androgen monotherapy respond after switching to androgen ablation (orchidectomy or LH-RH analogue). If there is relapse during androgen ablation, 25% respond by adding an anti-androgen (e.g. bicalutamide 50mg daily) to establish maximal androgen blockade (MAB). If MAB was used from initiation of hormone therapy, withdrawal of the anti-androgen paradoxically elicits a favourable response in 25% of patients.
A further rise in PSA may require third-line hormonal therapy such as the addition of oestrogens or corticosteroids. For example, diethylstilboestrol 1mg daily with 75mg aspirin for thromboembolic prophylaxis elicits a response in up to 60% of these patients. The mean duration of response is 4 months.
The prognostic factors for survival with androgen-independent disease are identical to the factors predicting response to hormone therapy, plus time from initiation of hormone therapy to initiation of chemotherapy and visceral metastasis status.

Cytotoxic chemotherapy
Systemic chemotherapy is offered to appropriate patients with androgen-independent metastatic disease, by the medical oncologist. Men with low-volume disease who have failed radical local treatment and hormone therapy are also candidates for chemotherapy. Elderly, frail, and infirm patients with significant bone disease, renal impairment, haematological and clotting abnormalities are unsuitable. Correction of renal and bone marrow dysfunction is necessary prior to treatment.

Symptom palliation
Symptom improvements are reported with cytotoxic chemotherapy. In a randomized trial of mitoxantrone plus prednisolone versus prednisolone alone, 29% in the combination group experienced a reduction in pain and analgesic use compared with 12% in the prednisolone alone group. PSA response did not predict palliative response. In another study, docetaxel plus prednisolone produced a pain reduction in 35% compared to 22% of patients given mitoxantrone and prednisolone, resulting in improved quality of life scores.

Cancer control
There are several reports of single-agent chemotherapy in the PSA era, most defining response as >50% decrease in PSA. Responses are reported in 20 ? 40% of patients with haematological toxicity (especially neutropenia) for most agents. Better responses (up to 75%) reported with newer combination regimes (e.g. estramustine phosphate plus docetaxel) but with greater toxicity. The median survival following chemotherapy ranges from 24 to 44 weeks. Results of two randomized studies comparing docetaxel with mitoxantrone plus prednisolone have shown a 2.4 ? 3 months? median survival advantage in favour of docetaxel.

Source: http://www.aligurtuna.com/prostate-cancer-treatment-6738.html

the last lecture kim jong un josh powell madonna halftime show linsanity the alamo north korea news