What happens when hormone therapy fails

If the PSA level increases while you are receiving total androgen blockade (LHRH agonist or antagonist plus androgen receptor blocker), first your doctor will stop the antiandrogen, which is called antiandrogen withdrawal (Figure 19). This causes the PSA to decrease in about 20% of patients, and the effect may last for several months to years. The LHRH analogue/antagonist therapy is continued. It is not clear why this antiandrogen withdrawal works. When the PSA rises after antiandrogen withdrawal, you may consider other forms of hormone therapy, such as ketoconazole, aminoglutethimide, estrogens, progestins, another antiandrogen, and chemotherapy.

Aminoglutethimide has produced a decrease in PSA in 48 to 80% of patients when it is given with a steroid (hydrocortisone) at the time of antiandrogen withdrawal. Side effects of aminoglutethimide include lowering of the blood pressure when you stand up (orthostatic hypotension), fatigue, gait disturbance (ataxia), and skin rash.

Ketoconazole is a medication that decreases androgen production from both the testicles and the adrenal glands and also works directly on the prostate cancer cells. In patients who have not responded to first-line hormone therapy (LHRH analogue or antagonist plus antiandrogen), Ketoconazole plus hydrocortisone decreases the PSA in about 15% of patients. In those who have not

Ketoconazole works quickly; its effects on testosterone level start 30 minutes after it is taken, and the testosterone level is decreased by 90% within 48 hours after therapy is started.

RRPX/Interstitial Seeds/EBRT

Increasing PSA with evidence of high probability of metastatic disease

LHRH Analogue or antagonist or Orchiectomy

Increasing PSA

Add antiandrogen

Increasing PSA

Withdraw antiandrogen

Increasing PSA

Aminoglutethimide

Ketoconazole

Chemotherapy

Corticosteroid

Figure 19 Treatment of increasing PSA after primary therapy (RRPX/ interstitial seeds/EBRT).

responded to antiandrogen withdrawal, ketoconazole plus hydrocortisone decreases PSA in about 75% of men.

Ketoconazole works quickly; its effects on testosterone level start 30 minutes after it is taken, and the testosterone level is decreased by 90% within 48 hours after therapy is started. The usual dose is 200 mg three times a day for the first week and then 400 mg orally three times a day thereafter. Some men respond to a lower dose of 200 mg three times a day as long-term therapy. The recommended dose of hydrocortisone is 20 mg at breakfast and 20 mg at dinner. If you develop ankle swelling or worsening of diabetes, then the dose is decreased to 20 mg in the morning and 10 mg in the evening, or simply 10 mg twice a day.

Side effects of ketoconazole include nausea and vomiting in about 15% of patients. Ideally, it should be taken between meals and not with antacids, Carafate, hista-mine2 blockers (ranitidine [Zantac], cimetidine [Tagamet], famotidine [Pepcid], nizatidine [Axid]), or protein pump inhibitors (omeprazole [Prilosec], lansoprazole [Prevacid], Nexus). It can also increase liver function blood abnormalities but rarely causes actual liver problems. Blood should be drawn to check the liver function regularly while you are taking ketoconazole. Ketocona-zole has the potential to interact with other medications that are metabolized by the liver, so check with your doctor if you are taking multiple medications to make sure that you are not taking anything that will have an interaction.

Corticosteroids (e.g., prednisone) can also decrease the production of androgens by the adrenal gland. They also have beneficial effects on appetite and energy level. Decreases in PSA have occurred in 20 to 29% of patients with hormone-refractory prostate cancer who are taking corticosteroids. Other corticosteroids, such as dexametha-sone and megestrol acetate, may also improve symptoms.

Chemotherapy has an increasing role in the management of men with hormone refractory/resistant prostate cancer. Docetaxel, a chemotherapeutic drug approved for hormone refractory prostate cancer, has been shown to increase survival with manageable side effects in men with hormone refractory prostate cancer, when compared

Hormone refractory

Prostate cancer that is resistant to hormone therapy.

Docetaxel

A type of chemotherapy, a taxane, that has been shown to be effective in hormone refractory prostate cancer.

to other forms of chemotherapy. The positive response noted with docetaxel has promoted researchers to evaluate additional chemotherapeutic drugs in ongoing clinical trials. Such trials allow some patients to participate in evaluating the effectiveness and safety of newer forms of chemotherapy. They may or may not prove to be beneficial for the participant, but the information gained from them allows oncologists to learn more about prostate cancer and effective treatment options. If you are interested in clinical trials, talk to your doctor about this or contact your local cancer center.

Provenge (produced by Dendreon) is an experimental vaccine therapy for advanced prostate cancer. Provenge is developed from one's own blood. A sample of blood is withdrawn and processed to extract certain immune cells called antigen presenting cells (APCs). Protein and prostatic acid phosphatase (PHP), found in most cancers, are then mixed. The prostate acid phosphatase is fused with an immune stimulating substance called GM-CSF. The mixture is then infused back into the patient over an hour's duration. This is repeated three times over the course of a month. Recent study results have demonstrated that those patients with advanced prostate cancer who received Provenge immunotherapy lived 4 months longer than patients with advanced prostate cancer receiving placebo in the trial.

29. What happens if my PSA rises after radical prostatectomy? After external beam radiation therapy (EBRT)? After interstitial seed therapy?

When the PSA rises after definitive therapy, such as EBRT, interstitial seed therapy, and radical prostatectomy, it is called PSA progression. In the absence of any identifiable cancer, it is called biochemical progression, because the only indicator of progression of the cancer is the PSA level. When the PSA is increasing after definitive therapy, your physician may want to restage you to determine where the cancer is. It is helpful in the decision-making process to determine whether the prostate cancer is confined to the prostate (in men who have had interstitial seed therapy or EBRT), the area where the prostate was (in postradical-prostatec-tomy patients), or the pelvis, or whether it has spread outside of the prostatic area. For example, if it has spread to the bones or lymph nodes higher up in your abdomen. Methods used in this staging process may be a bone scan (see Question 12), a ProstaScint scan, and/ or a CT scan of the abdomen and pelvis. In certain cases, the doctor may recommend a biopsy of the prostate, of the bladder neck area, or of other areas that may be likely to have cancer.

After a radical prostatectomy your PSA should decrease to an undetectable level by approximately 4 weeks postoperative. However, a detectable PSA level after this time does not mean that there is necessarily clinically significant recurrent prostate cancer. Some patients with a detectable PSA after radical prostatectomy do not have progression of their cancer because the PSA level is the result of the presence of benign prostate tissue at the margins of the resection (a very small amount of benign prostate tissue being left behind) or from a dormant residual focus of prostate cancer at a local or distant site. The definition of biochemical recurrence (evidence of recurrent prostate cancer based on PSA testing only) varies from a PSA of 0.2 ng/ml to 0.4 ng/ml post radical prostatectomy. In a large number of patients a biochemical recurrence of 0.2 is associated with a slowly progressive course.

Your doctor will look at a variety of factors to determine if the rising PSA is caused by benign tissue left behind at the time of surgery, locally recurrent prostate cancer that is amenable to radiation therapy, or metastatic prostate cancer that will require hormone therapy. Several investigators have looked at various criteria that may help distinguish local recurrence from distant metastases for patients with a rising PSA after radical prostatectomy. A Gleason score 8-10, seminal vesicle invasion, positive lymph nodes and a rapid PSA velocity (rate of change of the PSA) and a short disease-free interval after radical prostatectomy have been associated with a greater chance of metasta-tic disease.

Overall, about 35% of men who have had a radical prostatectomy will experience a detectable serum PSA within 10 years after surgery. The risk of developing metastatic disease after biochemical recurrence correlates with pathologic Gleason scores. Men with tumors of Gleason score < 8 have a 73% chance of remaining free of progression at 5 years after biochemical recurrence, compared with a < 10% probability in men with high grade tumors (Gleason 8-10). The length of time after surgery prior to biochemical recurrence was important in determining the risk of eventual distant failure for men with lower (5-7) and men with higher (8-10) Gleason scores. Using a cutoff of 10 months, the prostate specific antigen doubling time (PSADT) provides further substratification for men with Gleason scores of < 8. Men with a rapid rise in PSA (shorter PSA doubling time) have a greater risk of metastatic disease.

Several options are available, including watchful waiting, salvage EBRT, and hormone therapy.

Salvage Radiation Therapy

In males with a rising PSA after radical prostatectomy in whom the disease is felt to be locally recurrent, rather than metastatic, salvage radiation therapy is an option. The ASTRO (American Society for Therapeutic Radiology and Oncology) consensus panel concluded that the appropriate PSA seemed to be 1.5ng/ml for the institution of salvage radiation therapy. Others have demonstrated improved outcomes using a PSA threshold of 0.6. Gleason score 8-10, pre-radiotherapy PSA level > 2.0, negative surgical margin, PSA doubling time of 10 months or less, and seminal vesicle invasion are significant predictors of disease progression despite salvage radiation therapy. Conversely, a positive surgical margin suggests a greater likelihood that the recurrence is due to residual pelvic disease, therefore a patient with a history of a positive margin who develops an increasing PSA is most likely to benefit from salvage radiation therapy.

If your disease is metastatic, you are not a candidate or you are not interested in salvage radiation therapy, your doctor will discuss with you the options of watchful-waiting and hormone therapy.

Watchful Waiting

In one study, watchful waiting was used in men with a rising PSA after radical prostatectomy, and they were monitored until they had evidence of metastases. About 8 years after the radical prostatectomy, these men developed metastases, and an additional 5 years later, they died from their prostate cancer. In general, when watchful waiting is used for PSA progression after radical prostatectomy, the PSA is checked on an every 3 to 6 month basis to determine how quickly the PSA is rising (PSA velocity). If the doubling time, the time that it takes for

In general, when watchful waiting is used for PSA progression after radical prostatectomy, the PSA is checked on an every 3 to 6 month basis to determine how quickly the PSA is rising (PSA velocity).

the PSA level to double, is long (a year or longer), then the tumor is slow growing. If the doubling time is short (every 3 months), then the tumor is fast growing, and the patient would probably benefit from early treatment as opposed to continuing with watchful waiting.

Hormone Therapy

Hormone therapy tends to be used more commonly for men with recurrent cancer in whom the recurrence is believed to be outside of the pelvic area. Although hormone therapy may delay the progression of the prostate cancer, its impact on survival in this situation is not well known. Men with high-grade tumors (Gleason sum > 7) or with cancer in the seminal vesicles or lymph nodes at the time of radical prostatectomy and in whom the PSA rises within 2 years after prostatectomy most likely have distant disease and are candidates for hormone therapy or watchful waiting.

What if the PSA rises after EBRT?

Historically, three consecutive PSA rises after achieving a PSA nadir was felt to be indicative of biochemical recurrence after EBRT. However, in 2005, a consensus panel meeting was held, which concluded that a PSA value of 2 ng/mL greater than the absolute nadir represents the best revised definition of failure following external-beam radiation monotherapy. In individuals with biochemical failure after EBRT, the options of treatment include salvage prostatectomy, salvage cryotherapy, hormone therapy, and watchful waiting. The decision regarding the most appropriate therapy is based on the likelihood of the cancer being confined to the prostate.

Salvage Prostatectomy after EBRT

The ideal patient for a salvage radical prostatectomy after EBRT is one who is believed to have had prostate-confined disease initially at the time of EBRT and who is still believed to have organ-confined disease. Individuals in this group include those who have a Gleason score < 6, a low pretreatment PSA level (< 10 ng/mL), and low clinical stage tumor (T1c or T2a). At the time of the salvage prostatectomy, they should still have a favorable Gleason score, a low clinical stage, and, ideally, a PSA that is < 4 ng/mL. Salvage prostatectomy is a challenging procedure, and if you are considering this option, you should seek out an urologist who has experience with it because there is an increased risk of urinary incontinence, erectile dysfunction, and rectal injury with this procedure. Rarely, because of extensive scarring, it is necessary to remove the bladder in addition to the prostate, and a urinary diversion would be necessary. A urinary diversion is a procedure that allows urine to be diverted to a segment of bowel that can be made into a storage unit similar to a bladder or allows urine to pass out of an opening in the belly wall into a bag, similar to a colostomy.

Salvage Cryotherapy

One of the main uses of cryotherapy is in patients with a rising PSA after EBRT. In patients who have not responded locally to EBRT, approximately 40% who then undergo salvage cryotherapy will have an undetectable PSA level after cryotherapy, and 78% will have negative prostate biopsy results. It appears that a drop in the PSA to < 0.5 ng/mL after cryotherapy is associated with a good prognosis. In men with postcryotherapy PSA levels > 0.5 ng/mL, there is a higher likelihood that the PSA will increase or that the prostate biopsy result will be positive.

Hormone Therapy and Watchful Waiting

Use of these two options in patients with a rising PSA after EBRT is similar to their use in those with a rising PSA after radical prostatectomy.

Treatment of Rising PSA after Interstitial Seed Therapy

Treatment options for a rising PSA after interstitial seed therapy include salvage prostatectomy, EBRT, watchful waiting, and hormone therapy. It is important to remember that after interstitial seed therapy, there may be a benign rise in the PSA level, and this should not be misconstrued as being indicative of recurrent prostate cancer. In both interstitial seed and radiation therapy, for a rising PSA to be indicative of recurrent/persistent prostate cancer, it must rise sequentially on three occasions at least two weeks apart. The treatment options are dependent on the likelihood of the disease being confined to the prostate. Salvage prostatectomy for interstitial seed failure carries the same risks as with EBRT failures. The ability to use EBRT depends on the amount of radiation that was delivered at the time of the interstitial seeds and the likelihood of the disease being confined to the prostate.

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