230 CHAPTER 6 Urological neoplasia
Management of localized and radiorecurrent prostate cancer: cryotherapy and HIFU
These two minimally invasive treatments for localized prostate cancer are in use in many locations. Proponents claim that they are viable alternatives to radical surgery or radiotherapy and that they are options for salvage treatment of organ-confined recurrent disease following radical radiotherapy.
Furthermore, there is growing interest in “focal therapy,” whereby only a portion of the prostate is treated, sparing side effects that may be associated with more aggressive treatments.
Proponents note that of all local therapies, these are the only two that can be repeated if there is a recurrence. Cryotherapy is widely available, whereas HIFU is not yet FDA approved in the United States.
Cryotherapy
A transperineal ultrasound-guided cryoprobe delivers argon or liquid nitrogen at a temperature of –20*C to –40*C. When applied in two cycles of freeze–thaw, cellular necrosis occurs. The diameter of the ice ball is monitored using ultrasound; precautions must be taken to protect the urethra, external sphincter, and rectal wall, such as using warming devices.
An anesthetic is required; this is a day-case procedure that can be repeated.
Results
PSA nadir is usually achieved within 3 months; 25–48% of men with localized disease achieve a PSA nadir of <0.1 ng/mL in 3 months, and 96% of men achieve PSA <0.2 ng/mL within 6 months. Positive biopsies are observed in 8–25% of patients after cryotherapy.
Long-term results are promising but appear inferior to other standard therapies and are not endorsed by the AUA in their 2007 treatment guidelines for localized disease.1
Complications
These include ED (40–80%); incontinence (4–27%); LUTS due to urethral sloughing; pelvic pain; transient penile numbness; and rectourethral fistula (rare).
In the salvage setting, good short-term PSA responses are reported in 66% of men, at the expense of significant morbidity, including incontinence and urinary retention (70% each).
High-intensity focused ultrasound (HIFU)
HIFU has the potential of selective destruction of tissues at depth without damaging intervening structures. Tissue is heated to the point of
1 Gleave M, Klotz L, Taneja SS. (2009). The continued debate: intermittent vs. Continuous hormonal ablation for metastatic prostate cancer. Urol Oncol. 27(1):81–86.
MANAGEMENT OF RADIORECURRENT PROSTATE CANCER 231
coagulative necrosis by high-energy ultrasound transmitted to the prostate using a transrectal device. The tissue temperature is raised locally at this point (over 85°C).
With each firing of the probe, a cigar-shaped volume of damage is produced (a lesion). After one lesion is created, the focus is repositioned by computer guidance to create the next lesion with the same heating process. Lesions are placed side by side to create a continuous volume in which the tissue is necrosed. The rectal wall and the surrounding tissues are undamaged.
An anesthetic is required; this is a day-case procedure that can be repeated. The likelihood of morbidity is increased in the salvage treatment setting. Long-term results are awaited.
Complications
These include ED, urinary retention, stress incontinence, and recto-ure- thral fistula (rare).
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)