Chapter 091. Benign and Malignant Diseases of the Prostate (Part 8) For patients with a rising PSA after radiation therapy, salvage prostatectomy can be considered if the disease was "curable" at the outset, if persistent disease has been documented by a biopsy of the prostate, and if no metastatic disease is seen on imaging studies. Unfortunately, case selection is poorly defined in most series, and morbidities are significant. As currently performed, virtually all patients are impotent after salvage radical prostatectomy, and ~45% have either total urinary incontinence or stress incontinence. Major bleeding, bladder neck contractures, and rectal injury are not uncommon. In many cases, the rise in PSA after surgery or radiation therapy indicates subclinical metastatic disease. In these cases, the need for treatment depends, in part, on the estimated probability that the patient will show evidence of metastatic disease on a scan and in what time frame. That immediate therapy is not always required was shown in a series where patients received no systemic therapy until metastatic disease was documented. Overall, the median time to metastatic progression was 8 years, and 63% of the patients with rising PSA values remained free of metastases at 5 years. Factors associated with progression included the Gleason grade of the primary tumor, time to recurrence, and PSA doubling times. For those with Gleason grade ≥8 tumors, the probability of metastatic progression was 37, 51, and 71% at 3, 5, and 7 years, respectively. If the time to recurrence was <2 years and PSA doubling time was long (>10 months), the proportion with metastatic disease at the same time intervals was 23, 32, and 53%, vs. 47, 69, and 79% if the doubling time was short (<10 months). A difficulty with predicting the course of disease in the rising PSA state is that most patients receive some form of therapy before the development of metastases. Nevertheless, predictive models continue to be refined. PSA doubling times are prognostic for survival. In one series, all patients who succumbed to disease had PSA doubling times of 3 months or less. Most physicians advise treatment when PSA doubling times are 12 months or less. Metastatic Disease: Noncastrate Metastatic disease noncastrate refers to patients with metastases visible on an imaging study and noncastrate levels of testosterone. The patient may be newly diagnosed or have a recurrence after treatment for localized disease. Symptoms of metastatic disease include pain from osseous spread, although many patients are asymptomatic despite extensive spread. Less common are symptoms related to marrow compromise (myelophthisis), coagulopathy, or spinal cord compression. Standard treatment for noncastrate metastatic disease is to deplete androgens by medical or surgical means. Over 90% of male hormones originate in the testes; <10% are synthesized in the adrenal gland. Surgical orchiectomy is the "gold standard" approach but is least acceptable to patients. Medical therapies can be divided into agents that lower testosterone levels and antiandrogens that bind to the androgen receptor but do not signal (Fig. 91-3). Figure 91-3 Sites of action of different hormone therapies. Testosterone-Lowering Agents Medical therapies that lower testosterone levels include the gonadotropin- releasing hormone (GnRH) analogues, estrogens, and progestational agents. Estrogens such as diethylstilbestrol have fallen out of favor due to the risk of vascular complications such as fluid retention, phlebitis, emboli, and stroke. GnRH analogues (leuprolide acetate and goserelin acetate) initially produce a rise in luteinizing hormone and follicle-stimulating hormone followed by a downregulation of receptors in the pituitary gland, which effects a chemical castration. They were approved on the basis of randomized comparisons showing an improved safety profile (specifically, reduced cardiovascular toxicities) relative to diethylstilbestrol, with equivalent potency. The initial rise in testosterone may result in a clinical flare of the disease. These agents are therefore contraindicated in men with significant obstructive symptoms, cancer-related pain, or spinal cord compromise. Agents that lower testosterone are associated with an androgen-depletion syndrome that includes hot flushes, weakness, fatigue, impotence, loss of muscle mass, changes in personality, anemia, depression, and a reduction in bone density. The bone changes can be prevented by treatment with bisphosphonates along with vitamin D and calcium supplementation. GnRH analogues also lead to an alteration in body composition and to glucose intolerance. Many taking them develop the metabolic syndrome. . Chapter 091. Benign and Malignant Diseases of the Prostate (Part 8) For patients with a rising PSA after radiation therapy, salvage prostatectomy can be considered if the disease. included the Gleason grade of the primary tumor, time to recurrence, and PSA doubling times. For those with Gleason grade ≥8 tumors, the probability of metastatic progression was 37, 51, and 71%. antiandrogens that bind to the androgen receptor but do not signal (Fig. 91-3). Figure 91-3 Sites of action of different hormone therapies. Testosterone-Lowering Agents Medical therapies