How is metastatic disease diagnosed?

Metastatic disease should be distinguished from locally advanced disease. In the Whitmore-Jewett classification, it is stage D disease, and in the TNM classification, it is N1, N2, N3 or M1a, M1b, or M1c. From a practical standpoint, metastatic prostate cancer most commonly goes to the pelvic lymph nodes or bones.

Although a serum PSA above 10 ng/ml or a Gleason score of 8, 9, or 10 significantly increases the risk of metastatic disease, PSA and Gleason scores are fairly nonspecific determinants of metastatic disease. Most urologists today rely on radiographic information as the most reliable way to stage a patient with prostate cancer before initiating treatment.

CT and MRI have both been used to stage prostate cancer. From the literature, it would appear that an MRI is superior to a CT in detecting lymph node involvement. It has been demonstrated that an MRI is helpful if the prostate cancer has penetrated through the prostate capsule and extended locally. It is important to recognize that in order to determine local prostate cancer extension, an endorectal coil MRI rather than a transabdominal MRI should be performed.

A radionuclide bone scan is used to detect prostatic cancer metastases to the skeleton. A bone scan entails an intravenous injection of a radioactive isotope that is selectively taken up by metastases to the skeleton. After the patient is injected with the isotope, he is placed under a machine that scans his skeleton and the rest of his body for uptake of the radioisotopes. Old trauma to the skeleton, such as healed fractures, can sometimes cause false positive readings on the bone scan. It has been shown that patients with a serum PSA level of 10 ng/ml rarely, if ever, have bone metastases; thus, in such patients, a bone scan is rarely ordered.

What is an orchiectomy?

An orchiectomy refers to removal of the testicles. The type of orchiectomy that is performed for control of prostate cancer is referred to as a bilateral (both testicles) simple orchiectomy.

A bilateral simple orchiectomy is performed under local, spinal, or general anesthesia, depending on the preferences of the patient and the urologist. It is performed as outpatient surgery, and the patient goes home the day of surgery. A simple orchiectomy should be distinguished from a radical orchiectomy, which is performed for cancer of the testicle. A radical orchiectomy is performed through an inguinal incision, and the testicle and spermatic cord are removed together.

The reason for performing a bilateral simple orchiectomy for metastatic prostate cancer is that prostate cancer needs testosterone to grow. By removing the testicle, you remove 98% to 99% of the circulating testosterone, and this will cause most prostate cancers to go into remission, although hormone therapy alone rarely cures prostate cancer.

After a man undergoes a bilateral simple orchiectomy, he will experience decreased libido or sex drive and erectile function. He will also have hot flashes much like a woman does when she goes through menopause. Many men also lose some muscle mass and physical strength. After an orchiectomy, men will experience, to varying degrees, osteoporosis or thinning of bones.

The osteoporosis, if it becomes a problem, can be treated with medication. Finally, it may be obvious, but should be stated that men who undergo a bilateral orchiectomy no longer produce sperm and can no longer father children.

Gonadotropin-releasing hormone

A hormone made by the hypothalamus that in turn stimulates the pituitary gland; abbreviated GnRH.

What are GnRH agonists?

GnRH stands for gonadotropin-releasing hormone. GnRH is synonymous with LHRH or luteinizing hormone-releasing hormone. GnRH is released by the hypothalamus in the brain and acts on the pituitary gland to release luteinizing hormone, which then acts on the Leydig cells in the testicle to make testosterone. Circulating testosterone then stimulates prostate cancer growth.

Antiandrogen

Drugs that counteract the action of testosterone.

GnRH agonists initially actually stimulate luteinizing hormone release by the pituitary and subsequent testosterone production by the testicle. Therefore, treatment initially causes a rise in testosterone levels for the first week or so of treatment. This can actually result in a “disease flare” or exacerbation of bone pain from bone metastases if they are present in the patient. This “disease flare” from the transient rise of serum testosterone after initiation of GnRH therapy can be blocked by the use of antiandrogen drugs, which bind to androgen receptors of cells in the body, thereby rendering the cells “blind” to the effects of testosterone. We speak more fully about antiandrogens in Question “What are antiandrogens?”.

The reason that GnRH agonists work is that after about a week the GnRH agonists actually cause a downregulation of the receptors in the pituitary cells, which results in a decrease of LH production and subsequent testosterone levels.

GnRH agonists have been around for more than 3 decades and are an accepted alternative to bilateral orchiectomy. Recently, however, a drug, Plenaxis, which is a GnRH antagonist, has been developed. When a GnRH antagonist such as Plenaxis is used, there is an immediate inhibition of luteinizing hormone and testosterone suppression. Therefore, there is no “disease flare” or need for use of antiandrogens.

Bilateral orchiectomy, GnRH agonists, and GnRH antagonists are all equivalent therapeutically. Which therapy to use is basically a lifestyle choice for the patient. A bilateral orchiectomy is done once and is permanent. Although a minor surgical procedure, however, it is still surgery, and some men psychologically don’t like the idea of having their testicles removed.

GnRH agonists and antagonists have the same side effects as bilateral orchiectomy, such as decreased libido, erectile dysfunction, hot flashes, and loss of muscle mass, but avoid a surgical procedure. The GnRH agonists and antagonists are administered in the form of shots into the buttocks and come in varying doses so that the injections can be given every month, every 3 months, or once a year.

What are antiandrogens?

Antiandrogens are oral compounds that bind target cell androgen receptors, which prevent the uptake of testosterone. Antiandrogens are competitive inhibitors that prevent the binding of both DHT and testosterone to receptors in the cystoplasm of cells.

Two general classes of antiandrogens exist. The first type, steroidal antiandrogens, such as cyproterone acetate and megestrol acetate, are not commonly used in clinical practice any more. The second type, non-steroidal antiandrogens, such as eulexin (flutamide), nilutamide (nilandron), and bicalutamide (casodex), are much more commonly used clinically. Like any class of drugs, these drugs can have side effects that may include liver dysfunction, breast tenderness, breast enlargement (gynecomastia), and gastrointestinal side effects such as diarrhea, nausea, or vomiting. Sexual dysfunction is less common with the antiandrogens than with GnRH agonists or antagonists.

Today, antiandrogens are most commonly used with GnRH agonists. Some physicians, however, will treat patients with metastatic disease with antiandrogens as monotherapy or single agents.

Finally, the first antiandrogen drug that was ever used was estrogen. Estrogens are viewed as equivalent to testosterone from the point of view of the hypothalamus. Therefore, when a patient is given oral estrogens, the feedback “tricks” the hypothalamus into “thinking” that there is too much testosterone, and the hypothalamus responds by decreasing GnRH production, which subsequently decreases leuteinizing hormone and finally drops the serum testosterone.

Estrogen therapy, although relatively inexpensive, is rarely used today because of side effects. These side effects include loss of libido, sexual dysfunction, and decreased muscle mass, but more importantly, there are serious vascular side effects, which include deep venous thrombosis (blood clots in the legs) as well as strokes.

What is combination therapy?

Combination therapy refers to using a GnRH agonist or antagonist together with an antiandrogen. This results in what is known as total androgen blockade. This total androgen blockade is not transient, as is the case with the prevention of a “disease flare” after initiation of GnRH agonist therapy, but rather, combination therapy is often used on a permanent basis. The rationale behind this is the result of several studies that report that the use of combination therapy as compared with GnRH agonists or orchiectomy alone results in a slight survival advantage to the patient (see Table Results of combination hormonal therapy); however, not all physicians agree that combination therapy provides a significant advantage, and the patient should discuss these options thoroughly with his physician.

Table Results of combination hormonal therapy

No. Patients Treatment Median Time to Failure (mo) Median Overall Survival (mo)
603 leuprolide 13.9* 28.3*
  leuprolide + flutamide 1 16.5* 35.6*
327 orchiectomy 21.2* 28.8*
  goserelin + flutamide 44.2 43.9
174 orchiectomy 11.7 18.9
  orchiectomy + nilutamide 12.4 24.3
373 goserelin 12.0 32.0
  goserelin + flutamide 12.0 34.0

* Statistically significant

Goserelin = goserelin acetate

What other therapy is available for metastatic disease?

Other options are available for the treatment of metastatic prostate cancer. If a patient has symptomatic or painful skeletal metastases, local radiation therapy can be useful.

Also other drugs such as corticosteroids, ketoconazole, and aminoglutethimide are oral agents that can be tried if standard hormone therapy has failed.

Chemotherapeutic drugs are also being used for patients who have developed hormone-refractory prostate cancer — namely patients who were initially on hormone therapy but whose prostate cancer has mutated, which permits it to grow even in the face of low testosterone levels.

A variety of chemotherapeutic drugs have been used in the treatment of hormone-refractory prostate cancer. Some of these agents include cisplatin, vinblastine, doxorubicin, and mitoxanthrone. Before considering whether to use chemotherapy and which specific drugs and doses should be considered, a patient should have a thorough discussion with a medical oncologist.

 

Selections from the book: Kevin R. Loughlin, MD, MBA and John Nimmo, BA, MA, “100 Questions and Answers About Prostate Disease”, 2006.

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