Liarozole, a novel imidazole derivative, is the first retinoic acid metabolism-blocking agent (RAMBA) to be developed as differentiation therapy for human solid tumors. Most importantly, the drug has been shown to demonstrate anticarcinogenic and antitumor effects. Preclinical studies of liarozole have shown that it inhibits the growth of androgen-independent tumors, along with others, by inhibiting 4-hydroxylase, a cytochrome P450-dependent enzyme that is involved in retinoic acid catabolism. A recent study compared the ability of these two drugs to induce prostate-specific antigen (PSA) response in patients with metastatic prostate cancer that is progressing in response to first-line endocrine therapy. The multicenter, randomized trial consisted of 321 patients who had been recruited from 53 centers in 10 countries. Median age at the beginning of the trial was 72 years, with a range of 46 to 88 years. All patients except one were white. Identified as prognostic factors for survival were baseline hemoglobin, alkaline phosphatase, PSA, duration of response to first-line treatment, and performance status. Because most patients with prostate cancer do not present assessable lesions, it is difficult to evaluate objective tumor response. As a result, prostate-specific antigen (PSA) was used in this study as a marker for tumor response.

Liarozole was started at 150 mg twice daily and then increased 300 mg twice daily for the remainder of the treatment. The cyproterone acetate (CPA) dose used was 100 mg twice daily from the start of the study and remained the same unless dosage adjustments were necessary according to prescribing information. Treatment continued until clinical progression was shown or a serious adverse event occurred. Patients were followed up until death. The trial was analyzed after 232 deaths.

Prostate-specific antigen (PSA) responders were more prevalent in the liarozole group (20%) than in the cyproterone acetate group (4%), p < 0.001. PSA stabilization occurred in 64% of patients in the liarozole group. Changes indicative of continuous progression were observed in 17% of patients treated with liarozole, in contrast to 40% of patients in the cyproterone acetate group. The response was not affected by previous use of antiandrogens in either treatment group.

Prostate-specific antigen (PSA) response occurred by week 12 in 90% of responding patients. The median time to progression was 4.6 months in the liarozole group and 3.6 months in the cyproterone group. Patients who had a PSA response experienced a median survival of 25 months. Those who experienced stabilization survived for 14 months, and patients with continuous progression survived for 7 months. PSA responders had a 57% lower risk of dying as compared with nonresponders.

When comparing the two drugs, after adjustment for baseline prognostic factors, the study showed that patients treated with liarozole survived longer and had a 26% lower risk of dying than did patients on cyproterone acetate. Liarozole treatment resulted in a significantly better PSA response (20% of patients compared with 4% of the cyproterone group). Also, PSA stabilization was observed in 64% of the liarozole group. Participants in both groups of the trial reported various adverse events. In the liarozole group, the most common problems were dry skin, pruritus, rash, nail disorders, and hair loss. Patients undergoing cyproterone acetate treatment suffered from edema, nausea, vomiting, and fatigue. For the most part, these conditions were mild to moderate. Adverse events caused withdrawal from treatment for 88 patients in the liarozole group and 63 patients in the cyproterone acetate group. Most of the withdrawals occurred because of cancer-related events such as skin disorders, nausea, and vomiting.

Patients with metastatic prostate cancer usually complain of bone pain due to skeletal involvement. Advanced prostate cancer patients will also present with signs and symptoms of lymphadenopathy, lower extremity edema, renal failure, visceral metastases, anemia and cachexia. Prostate cancer and these accompanying medical conditions can lead to a lot of pain and poor performance status.

In conclusion, this trial shows that prostate-specific antigen (PSA) response is an effective way to measure the clinical benefits of prostate cancer therapies. Patients who experienced this response lived longer, had less pain, and an improvement in quality of life. Liarozole was shown to be more effective than cyproterone acetate in achieving PSA response and in treating relapsed prostate cancer.

The PCPT trial enrolled men older than 55 with a prostate specific antigen (PSA) value less than 3 ng/mL and an American Urologic Society (AUS) score below 20. The men in this trial were randomly assigned to receive finasteride 5 mg or a matching placebo daily and followed for seven years with annual PSA and digital rectal exam (DRE) screening, with 9,459 men assigned to the placebo arm. After seven years of PSA and DRE screening, the men who never had a PSA higher than 4 ng/mL, an abnormal DRE, prostate surgery of any type, and had a prostate biopsy (minimum of six samples) at the end of the study were evaluated for cancer prevalence. There were 2,950 men, ages 62 to 91, who met these criteria, and in 449 (15.2%) of those men, prostate cancer was detected. Always controversial, the use of the Analysis of the patient demographics revealed that age and race did not predict those who would have prostate cancer, but a positive family history (affected brother, father, or son) did correlate with an increased risk of prostate cancer (p = 0.004). The mean prostate specific antigen (PSA) score of men with cancer was 1.78 + 0.92 ng/mL, significantly different from those without cancer at 1.34 + 0.86 ng/mL (p = 0.001). The mean annual rise in PSA (0.32 to 0.46 ng/mL) was also significantly higher in men with prostate cancer (p = 0.001).

Since prostate specific antigen (PSA) was first described in 1979, the ability of the test to predict clinically significant prostate cancer has been hotly debated. What is a normal versus an abnormal PSA value; was the test sensitive and able to reliably detect it; and what would the costs be from false-positive results in patient harm and to society in unnecessary procedures performed? — all have been questioned over the past two decades. A prostate specific antigen (PSA) level higher than 4 ng/mL is the standard indicator for a man likely to have clinically significant prostate cancer. For men with a PSA level between 4 and 10, approximately 25% will have prostate cancer. For PSAs higher than 10, this number rises to nearly 50% of patients having prostate cancer detectable by biopsy.

Even with new data on the prevalence of prostate cancer in men with a prostate specific antigen (PSA) below 4, this information does not provide any additional direction on whom to treat. The finding that 15% of men with normal PSA values have early-stage prostate cancer requires the review of prostate screening practices, more importantly because the incidence of cancer likely to be aggressive (Gleason score greater than 7), although low at 2.3%, was sprinkled throughout the PSA distribution. Not all of these patients would undergo invasive therapy, because depending on the patient’s age and life expectancy, treatment may range from watchful waiting to prostatectomy for this stage of cancer.

What to do now? It was already known, based on autopsy studies, that 15% to 60% of men ages 62 to 91 had unrecognized prostate cancer.However, none of these men diagnosed at autopsy actually died of their cancer. Thus, what patients really need to know is what the best screening method is to ensure that men who undergo biopsies and other therapies are at risk for cancer-driven effects that will affect the length and quality of their life. While a small number of the cancers found in this study were aggressive based on their Gleason score, the low prostate specific antigen (PSA) values indicate a small volume of disease that is unlikely to imminently impact a patient’s quality of life. Further limitations of this study are that its results apply only to Caucasian men older than 62. The minimum age of these patients was 62, and minorities were poorly represented in the final sample. In the otherwise asymptomatic male with a PSA of 0 to 4 ng/mL, current recommendations still continue with close follow-up of AUS score, digital rectal exam (DRE), and prostate specific antigen (PSA) to guide definitive therapy if indicated in that specific individual. The information from this study further emphasizes the critical need for patients’ annual follow-up with their oncologist or urologist to facilitate medical interventions if and when they are needed. Meanwhile, new biomarkers and stratification schema are being pursued as oncologists work to further define better diagnostics and care algorithms in the treatment of those with this challenging disease.

The leading test to detect prostate cancer is “clinically useless” at determining the size or severity of a man’s tumor, and is only of “limited” value at predicting cure rates from surgery to remove the diseased gland, a new study says.

The test, which measures a blood enzyme called prostate-specific antigen (PSA), is likelier to find benignly enlarged prostates and prompt overly aggressive treatment, according to the scientists who conducted the study.

The study, which appears in the January issue of the Journal of Urology, “is quite a disappointment,” says Dr. John McNeal, a Stanford University pathologist and a co-author of the paper.

“We used to think [PSA testing] was good. But what we would like it to tell us is whether a PSA that is not much elevated is elevated because of [normal prostate growth] or whether it’s elevated because of prostate cancer.” And the protein, at least at moderate levels, can’t do that, McNeal says.

Dr. Peter Albertsen, chief of urology at the University of Connecticut in Farmington, says the study “is not going to knock prostate-specific antigen (PSA) screening off the map by any means.”

However, Albertsen adds, PSA testing is undergoing a crisis of confidence similar to that of screening mammography, another exam whose value has come under questioning.

“I think there’s enough tantalizing evidence to think” that routine prostate-specific antigen (PSA) screening saves lives, Albertsen adds. But there’s not enough evidence to be sure.

Almost 190,000 American men are diagnosed annually with prostate cancer, and 30,000 will die from it, according to the American Cancer Society. Prostate-specific antigen (PSA) testing is widespread in men over age 50, but no study has proved that it saves lives by helping doctors identify prostate tumors when they’re still curable.

One reason: prostate cancer grows glacially. So while most men will die with cancer of the gland, relatively few will die of it. Aggressive treatment of slowly growing tumors may therefore cause more harm than good, some experts argue.

In the latest study, Dr. Thomas Stamey, a Stanford University urologist, and his colleagues studied the relationship between PSA scores in 875 men who underwent radical prostate surgery, in which the gland was completely removed, between 1984 and 1997.

Stamey’s group analyzed prostate-specific antigen (PSA) readings taken from many of the men both before and after their operation.

The largest tumors did produce extremely elevated PSA levels, topping 22 nanograms per milliliter of blood. Scores of more than 9 ng/ml were somewhat associated with aggressive disease, as measured by standard gauges of malignancy.

But for prostate-specific antigen (PSA) values between 2 and 9 ng/ml, the culprit was often not cancer but benign prostatic hypertrophy (BPH), or normal swelling of the gland.

Nor did PSA testing predict cure rates: Surgery success was the same for men whose pre-operation PSA was lower than 4 ng/ml as it was for those with a score of 10 ng/ml.

The prostate-specific antigen (PSA) enzyme is secreted by cells in the prostate, and mildly elevated values often reflect a larger than normal gland. BPH is as common as cancer, a fact many men don’t realize.

Scientists have been trying to tweak the prostate-specific antigen (PSA) test to make it more reliable, but whether these new techniques will be more sensitive to cancers remains a mystery. In fact, PSA is a misnomer, since the enzyme is secreted not only in the prostate but in the breast as well.

What To Do

Every man has a prostate-specific antigen (PSA) level, and any score between one and four could be totally normal, McNeal says. The tricky part comes in deciding what to do if the test comes back between 7 and 8. Despite his group’s findings, McNeal says he would probably undergo a biopsy if his own PSA test were in that range.

And saw palmetto berry extract, listed by Consumer Reports in the US as a potentially helpful herb, could be just what the doctor ordered.

As many as a third of all men over 50 may suffer from benign prostate hyperplasia, experts estimate. The condition is not cancerous and simply means that the tissue of the prostate is inflamed and swollen.

Saw palmetto berry extract can help the tissue to shrink, allowing for more regular urination patterns – and with few side effects, as long as you use it with a doctor’s help, experts say.

How does it work? No one is exactly sure, but herbalists have an idea.

“It seems to affect the hormone levels in the genital area,” says Kara Dinda, director of education for the American Botanical Council in Austin, Texas.

And while the effects of the herb on men’s prostates seem fairly well documented, its effect on women is not known. Since hormones may be affected, it’s especially important that pregnant and lactating women not use the herb.

Use of this herb, which derives from the berries of the dwarf palmetto tree which is grown largely in Florida, dates back to the 1700s among Native Americans. Rigorous studies supporting use of the herb are far more recent.

According to an article in the Minneapolis Star Tribune, for example, a 1996 study of 1,098 men in the US showed that saw palmetto berry extract is at least as effective as a popular prescription drug – and produces fewer side effects, including impotence. And The Daily Telegraph reports that close to 90 per cent of men in Germany with benign prostate hyperplasia are treated with plant extracts, and saw palmetto berry extract tops the list.

One concern among doctors has been that use of the herb or a product containing it might affect PSA levels, by which prostate cancer can be diagnosed. But an editorial in Urology said that US herb specialist Varro Tyler and a UCLA urologist showed that use of the herb did not affect any tests of the prostate, including the PSA.

Side effects? They’re relatively minor: stomach problems, headaches and, with large doses, diarrhea.

One caveat: A Boston Globe story reported that a 1998 review of the herb suggested that other new prostate medications may in fact be more effective than saw palmetto berry extract.

What To Do

This herb sounds promising. Men should ask their GP for further information, however. “Herbs produce chemicals,” says Erica Kipp, manager of the Plant Research Laboratory for the New York Botanical Garden. “I think people have the misconception that anything from a plant is natural and good and benign – and this is not necessarily the case.”

“Serum PSA drawn preoperatively does not reflect a change in cure rate until the level reaches nine ng/ml. The cure rates by radical prostatectomy are all the same between two and nine ng/ml,” stated Dr. Thomas A. Stanley of Stanford University in Palo Alto, California. He presented his data and conclusions to fellow urologists in a special lecture at the meetings.

Dr. Stanley looked at long-term data from 695 men with prostate cancer. As expected, among men with preoperative prostate specific antigen levels above 10 ng/ml, higher PSA levels predicted lower cure rates. But he looked specifically at those men whose PSA levels were between two and nine ng/ml. His surprising findings: the cure rate was about 80 percent across the whole range.

“PSA is a very good marker above nine ng/ml,” stated Dr. Stanley. “But something else is driving prostate specific antigen other than the cancer between two and nine”. And that something else, he reasons, is benign prostate enlargement.

“I believe our diagnosis of prostate cancer in men with a prostate specific antigen between two and nine ng/ml is pure serendipity, unrelated to morphologic variables of the cancer or to its cure rate,” says Dr. Stanley. It is well known that benign prostatic hyperplasia (BPH), a non-cancerous condition, also elevates prostate specific antigen. The researcher noted that among men with prostate cancer, PSA levels did not reflect either cancer stage or size of the tumor.

“The bottom line is that we urgently need a far better marker for prostate cancer than prostate specific antigen,” Dr. Stanley concluded.

If the findings are supported by more research, the clinical approach to treating men with prostate cancer could change: men with lower prostate specific antigen levels might be told to delay surgery “because the chance of cure should be about 80 percent until prostate specific antigen crosses the nine ng/ml threshold,” he stated.

According to researchers from the University of Texas Southwestern Medical Center at Dallas, prostate-specific antigen test results can predict the risk of acute urinary retention (AUR) and the need for prostate surgery in men with benign prostatic hyperplasia (BPH). Benign prostatic hyperplasia refers to a non-cancerous enlargement of the prostate gland and is commonly found in men over age 50. Although not life-threatening, an enlarged prostate may block the urethra and make the passage of urine difficult. It can also lead to acute urinary retention, a condition in which urination becomes nearly blocked.

In this study, investigators compared the prostate-specific antigen test results of over 3,000 older men with their incidence of AUR and BPH. They found that up to 20 percent of men with high PSA levels experienced either AUR or BPH-related surgery. However, in men with low prostate-specific antigen values, fewer than eight percent experienced either of those conditions. They also noted that when patients with high PSA scores are treated with finasteride, a drug used in benign prostatic hyperplasia to shrink the prostate gland, their risk for developing acute urinary retention or requiring surgery was reduced by up to 60 percent.

The authors concluded that a patient’s prostate-specific antigen values can help doctors predict the risk of BPH-related outcomes and identify appropriate therapy for benign prostatic hyperplasia.

Introduction

Testosterone suppression or hormonal therapy is commonly used for the palliative treatment of patients with advanced prostate cancer. Reduction of testosterone levels results in a therapeutic response in some patients, including reduced or halted growth of prostate cancer cells and relief of symptoms such as pain and urinary difficulties. The most common means of achieving such as decrease has been via frequent injections with leuprolide.

ALZA Corporation is now producing Viadur, an implant that delivers leuprolide steadily for up to one year. The FDA approved Viadur on March 3 2000. Viadur is implanted in the patient’s inner upper arm once a year in his doctor’s office, and provides continuous 12-month testosterone suppression. After the first year of therapy, the implant is removed and a new one inserted.

Viadur: How It Works

Viadur is a small titanium implant filled with 72 mg of leuprolide acetate (65 mg leuprolide free base), an agent in the class of drugs known as luteinizing hormone-releasing agonists. Leuprolide acetate acts as a potent inhibitor of gonadotropin secretion, resulting in a reduction in the amount of testosterone produced by the body.

ALZA’s DUROS implants are miniature titanium cylinders designed to provide continuous, osmotically-driven delivery of leuprolide for up to one year. Titanium, a material with excellent tolerability to human tissue, has long been used in implantable medical devices. The cylinder protects the drug from degradation in the body.

Viadur: Clinical Study Results

The efficacy of Viadur was established in two open-label, multicenter clinical studies of 131 patients with advanced prostate cancer who were treated with Viadur and evaluated for up to two years. Two-thirds of the patients had stage C or less advanced disease. Serum testosterone levels were evaluated in patients who had received either one or two implants. Following the initial insertion of the implant, mean serum testosterone levels increased from 422 ng/dl at baseline to 690 ng/dl on day 3, and then decreased to below baseline by the second week. Serum testosterone decreased below the 50 ng/dl castrate threshold by week 4 in 99% of patients. Once serum testosterone suppression was achieved, it remained below the castrate threshold for the duration of the treatment phase.

Most patients (118) had a new implant inserted for a second year of therapy following the removal of the first implant after one year. No patients experienced a clinically significant increase in serum testosterone following removal of the first implant and insertion of the second.

Serum prostate-specific antigen (PSA) was monitored as a secondary endpoint in the clinical studies of Viadur. Serum prostate-specific antigen decreased in all patients after they began treatment with Viadur. At six months, prostate-specific antigen concentrations decreased from baseline by at least 90% in 74.2% of 97 evaluable patients.

Viadur: What the Patient Should Know

The most common side effects associated with Viadur were those expected with other drugs in its class, including vasodilation (67.9%), asthenia (7.6%), gynecomastia (6.9%), depression (5.3%), and sweating (5.3%). Local reactions at the implantation site included bruising (34.8%) and burning (5.6%). Most implantation site reactions began and resolved in the first two weeks. Patients should avoid heavy lifting and physical activity for 48 hours after the implantation.

Patients may experience a worsening of symptoms when serum testosterone increases at the beginning of treatment. Such symptoms may include bone pain, neuropathy, hematuria, or ureteral or bladder outlet obstruction.