Материал: Oxford American Handbook of Urology ( PDFDrive )

232 CHAPTER 6 Urological neoplasia

Management of locally advanced nonmetastatic prostate cancer (T3–4 N0M0)

EBRT

EBRT in combination with hormone therapy has consistently demonstrated better outcomes than those with EBRT alone, which is associated with a 15–30% 10-year survival. In a European randomized study1 the hormone therapy group received LHRH analogues for 3 years starting at the time of EBRT. Their 5-year overall survival was 79% compared to 62% in the group treated with EBRT alone; the 5-year disease-free survival was 85% compared to 48%.

There are potential advantages in starting hormone therapy prior to EBRT as has been performed in other positive studies. The optimal timing and duration of hormone therapy in this setting remain unclear, but most agree that 6 months is inadequate, and 24–36 months should be considered a standard of care in high-risk disease.1

Hormone therapy

Hormone therapy alone is another option in elderly patients or those unwilling to consider radiotherapy, but its risk and benefit ratio are not clear. Outside the United States, a nonsteroidal antiandrogen (e.g., bicalutamide 150 mg) regimen is often used.

In the U.S., standard androgen ablation involves orchiectomy or LHRH analogue or antagonist. However, discussion should include the point at which hormone therapy is not a treatment offered with curative intent.

A randomized trial of hormone therapy alone vs. EBRT plus hormone therapy demonstrated that the hormone-only regimen was inferior to the combination treatment.2

Watchful waiting or active surveillance

This is also an option for nonmetastatic T3 disease in an elderly asymptomatic man who may wish to avoid side effects of treatment.

Palliative treatment of locally advanced disease

Palliative TURP or medical therapy for LUTS or retention may be necessary. Incontinence can be due to sphincter involvement, though bladder outflow obstruction and instability should be considered: a urinary convene sheath or catheter may be required.

Percutaneous nephrostomies or ureteral stents are occasionally necessary for ureteral obstruction.

1 Bolla M, de Reijke TM, Van Tienhoven G, et al. (2009). Duration of androgen suppression in the treatment of prostate cancer. N Engl J Med 360(24):2516–2527.

2 Widmark A, Klepp O, Solberg A, et al. (2009). Endocrine treatment, with or without radiotherapy, in locally advanced prostate cancer (SPCG-7/SFUO-3): an open randomised phase III trial. Lancet 373(9660):301–308.

MANAGEMENT OF ADVANCED PROSTATE CANCER 233

Management of advanced prostate cancer: hormone therapy I

Metastatic disease is the cause of nearly all prostate cancer–related deaths. 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 used in cases of castration-resistant prostate cancer.

The concept of hormone therapy was realized in 1941 when Huggins and Hodges reported favorable acid and alkaline phosphatase responses in prostate cancer patients who were castrated or given estrogens.

Hormone dependence of prostate cancer

Of circulating androgen, 95%, mainly testosterone, is produced by the Leydig cells of the testes under the influence of luteinizing hormone (LH). The anterior pituitary synthesizes LH, stimulated by LH-releasing hormone (LHRH) produced by the hypothalamus. The remaining 5% of circulating androgen is synthesized by adrenal cortex from cholesterol.

Testosterone is metabolized to the more potent dihydrotestosterone (DHT), by types 1 and 2 5A-reductase (5AR) enzymes. DHT binds to the androgen receptor, travels to the cell nucleus, and exerts its positive effect on cell growth and division in the androgen-sensitive cell.

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 the majority of patients. However, most will still die within 5 years because of the development of androgen-independent growth, a state now commonly referred to as “castration resistant disease.” This is considered due to growth of androgen-independent cell clones rather than to a dedifferentiation of previously androgen-dependent cells.

Traditionally, the mean time to disease progression after androgen deprivation is 14 months in men with metastatic disease, although more recent series suggest that this time is actually longer.

Prognostic factors

Predictors of poor hormone therapy response include the following:

•t5 metastatic lesions at presentation

•Elevated alkaline phosphatase at presentation

•Anemia at presentation

•Poor performance status 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 (a PSA nadir (= lowest value) of <0.1 ng/mL predicts a long-term response)

234 CHAPTER 6 Urological neoplasia

Management of advanced prostate cancer: hormone therapy II

Mechanisms of androgen deprivation

•Surgical castration: bilateral orchiectomy

•Medical castration: LHRH agonists, LHRH antagonists, estrogens

•Antiandrogens (steroidal or nonsteroidal): androgen receptor blockade at target cell

•Maximal androgen blockade (MAB): medical or surgical castration plus antiandrogen

Both forms of castration (androgen ablation or deprivation are the preferred terms today) have equivalent efficacy, so patients should be given the choice. Estrogens are no longer first-line agents because of the significant cardiovascular morbidity. Antiandrogens alone are less effective in treating metastatic disease, but equivalent for nonmetastatic 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.

5AR inhibitors such as finasteride or dutasteride are not used in the treatment of prostate cancer but appear to have a role in prevention.

Bilateral orchiectomy

This is a simple procedure usually carried out under general anesthesia. Through a midline scrotal incision, both testes may be accessed. The testes are entirely removed or some prefer to incise the tunica albuginea of each testis and the soft tissue content is removed, after which the capsule is closed.

The epidiymes and testicular appendages are preserved; this allows some fullness to remain in the scrotal sac and may psychologically benefit the patient.

Postoperative complications include scrotal hematoma or infection (both rare). Serum testosterone falls within 8 hours to <0.2 nmol/L.

LHRH agonists

Developed in the 1980s, LHRH agonists give patients an alternative to bilateral orchiectomy, with which they are clinically equivalent. They are given by subcutaneous (SC) or intramuscular (IM) injection, as monthly or 3-, 6-, or 12-month depots. Some examples of these peptides include goserelin, triptorelin, histrelin, and leuprolide (see Table 6.6). Nasal forms are available outside the U.S.

If the anterior pituitary is desensitized to the pulsatile release of natural LHRH by the analogue of LHRH, it switches off LH production, although serum testosterone rises in the first 14 days because of a surge of LH. This can result in “tumor flare,” manifest in 20% patients with increased symptoms, including catastrophic spinal cord compression. To prevent this, cover with antiandrogens is recommended for a week before and 2 weeks after the first dose of LHRH agonist.

An injectable LHRH antagonist (degarelix) (Table 6.6) rapidly reduces serum testosterone by blockade of the LHRH receptors.

Copyright © MedReviews®, LLC. Reprinted with permission of MedReviews®, LLC. Gomella LG (2009). Effective testosterone suppression for prostate cancer: is there a best castration therapy?. Rev Urol. 11(2):52–60. Reviews in Urology is a copyrighted publication of MedReviews®, LLC. All rights reserved.

236 CHAPTER 6 Urological neoplasia

Side effects of bilateral orchiectomy and LHRH agonists/antagonists

•Loss of sexual interest (libido) and ED

•Hot flushes and sweats can be frequent and troublesome during work or social activity

•Weight gain and obesity

•Gynecomastia

•Anemia

•Cognitive (mood) changes

•Metabolic syndrome (increased blood glucose and lipid profile)

•Osteoporosis and pathological fracture secondary to osteoporosis may occur in patients on long-term treatment.

Antiandrogens

These are administered as tablets. Examples include the nonsteroidal antiandrogens such as bicalutamide (50 mg daily for MAB, in combination with LHRH analogues or orchiectomy; 150 mg daily as monotherapy [not FDA approved in the U.S.]), flutamide, nilutamide, and the steroidal antiandrogen cyproterone acetate.

Bicalutamide monotherapy raises the serum testosterone slightly, so sexual interest and performance are often maintained.

Side effects include frequent gynecomastia, breast tenderness, and occasional liver dysfunction; flutamide can cause GI upset.

At its full dose, cyproterone acetate may cause reversible dyspnea; it may be used at 50 mg bid for treatment of castration-induced hot flushes.