The four-year study found that dutasteride (Avodart®) significantly reduced the chances that men would be diagnosed with the tumors that are most often treated excessively: those that fall in the mid-range of aggressiveness. These tumors, which account for the majority of all prostate cancers, grow unpredictably. This uncertainty leads many men to opt for surgery or radiation therapy – treatments that can lead to incontinence and impotence.

“Dutasteride may potentially offer many thousands of men a way to reduce their risk of being diagnosed with prostate cancer,” says the study’s lead author Gerald Andriole, MD, chief of urologic surgery at Washington University School of Medicine in St. Louis. “This means more men could avoid unnecessary treatment for prostate cancer along with the costs and harmful side effects that can occur with treatment.”

Andriole chaired the steering committee that oversaw the trial, known as REDUCE (Reduction by Dutasteride of Prostate Cancer Events), which was conducted at 250 sites in 42 countries. It is the first to evaluate chemoprevention for prostate cancer in men at increased risk of disease. The study was funded by GlaxoSmithKline, the manufacturer of Avodart®.

The trial involved 8,231 men ages 50-75, who were randomly assigned to receive a placebo or a daily 0.5 mg dose of dutasteride, a drug that is known to shrink the prostate. Men in the study were considered to be at increased risk for prostate cancer because they had elevated PSA levels (2.5 ng/ml – 10 ng/ml) but no evidence of cancer on biopsies performed within six months of enrolling in the trial.

“Many men every year are in the situation of having elevated PSA levels but a negative biopsy,” Andriole explains. “We know from experience that many of these men are likely to have microscopic prostate tumors that were missed by their original biopsy.”

The investigators performed scheduled biopsies on the men two years after they enrolled in the study and again after four years. Over all, 659 men (19.9 percent) taking dutasteride were diagnosed with prostate cancer, compared to 858 men (25.1 percent) taking a placebo. None of the men in the study died of prostate cancer.

Among men with a family history of prostate cancer, the drug reduced the relative risk of a prostate cancer diagnosis by 31.4 percent.

“The most likely explanation for the study’s results is that dutasteride is keeping tumors small or even shrinking them to the point that they are unlikely to be detected by a biopsy,” says Andriole, who also treats patients at Barnes-Jewish Hospital and the Siteman Cancer Center.

Dutasteride was most effective at reducing the risk of medium-grade tumors, defined as 5-6 on the Gleason scale. The Gleason scoring system measures tumor aggressiveness based on biopsy results and can range from 1-10, with 10 being the most aggressive. Over the study’s four years, 70 percent of all men diagnosed with prostate cancer had Gleason 5-6 tumors, roughly the same percentage doctors see in clinical practice. These included 617 men (18.1 percent) taking a placebo and 437 men (13.2 percent) taking dutasteride, a statistically significant difference.

Dutasteride was approved by the U.S. Food and Drug Administration in 2001 for the treatment of benign prostatic hyperplasia (BPH). The condition causes frequent urination that is difficult or painful because the swollen prostate gland blocks urine flow. Dutasteride is not approved for prostate cancer prevention.

The investigators found no significant increase in aggressive, high-grade tumors (defined as a Gleason score 7-10) among men who took dutasteride over four years. There were 220 men (6.7 percent) on dutasteride with aggressive, high-grade tumors, compared with 233 men (6.8 percent) on a placebo. However, they noted a disparity in the most aggressive tumors (defined as a Gleason score 8-10) among men taking dutasteride in years three and four of the study: 12 such tumors were detected in the dutasteride group versus one in the placebo group.

The study was designed so that men were withdrawn after they had a positive tumor biopsy. “But it’s likely that if the men in the placebo group who were diagnosed with Gleason score 5-7 tumors in years one and two had remained in the study and been biopsied again, some of their tumors likely would have been upgraded to a Gleason 8-10 in study years three and four,” Andriole says. “This so-called tumor upgrading has been observed in other studies.”

Moreover, he says, it is well recognized that Gleason scores based on biopsies are more accurate in men on dutasteride or the similar BPH drug finasteride (Proscar®), who have smaller prostates, than in men with larger, growing prostates, where a needle biopsy is more likely to miss a tumor and to underestimate the true Gleason score.

The observation regarding high-grade tumors parallels that in the earlier Prostate Cancer Prevention Trial, which evaluated finasteride in men with no increased risk of the disease. While finasteride was found to lower overall prostate cancer risk, there were more aggressive tumors detected by biopsies in men taking that drug. Later analyses adjusting for prostate size at the time biopsies were performed showed no increase in high-grade tumors.

When researchers in the current study accounted for prostate size at the time of biopsy, their analysis (published in supplementary materials to the NEJM article) also indicated fewer aggressive cancers among men receiving dutasteride. Despite these considerations, the investigators could not completely rule out that some of the most aggressive tumors were due, in part, to dutasteride.

Like finasteride in the Prostate Cancer Prevention Trial, dutasteride also improved the accuracy of the PSA test to detect prostate cancer, particularly when tumors are aggressive, Andriole and his colleagues noted in unpublished results. Dutasteride is known to reduce PSA levels by 50 percent.

“If PSA levels started to rise even slightly in a man taking dutasteride, he had an increased chance of being diagnosed with prostate cancer, compared with men in the placebo group who tended to have PSA levels that naturally fluctuated,” he said.

Dutasteride blocks two forms of the enzyme 5-alpha reductase, which converts the hormone testosterone into dihydrotestosterone. In contrast, finasteride inhibits only one form of the enzyme. Dihydrotestosterone is known to drive benign prostate growth and the development of prostate cancer.

Last year, both the American Society of Clinical Oncology and the American Urological Association issued guidelines suggesting that healthy older men who already are taking a 5-alpha reductase inhibitor for BPH or undergoing regular prostate cancer screening tests discuss with their doctors long-term use of the drug for prostate cancer prevention.

The REDUCE investigators also found that dutasteride reduced the risk of urinary retention, urinary tract infection and the need for surgery to alleviate BPH, compared with the placebo.

The two most common side effects associated with dutasteride were low rates of erectile dysfunction and decreased libido, which are consistent with earlier studies of the drug.

While rare, the investigators also noted more occurrences of cardiac failure among men taking dutasteride, compared with those taking a placebo. Thirty (0.7 percent) men on dutasteride and 16 (0.4 percent) men on a placebo received a diagnosis of cardiac failure. There was no significant difference between the two groups in the occurrence of or deaths from cardiovascular problems.

Supplemental data to the NEJM article indicated that cardiac failure was more likely to occur in men taking both alpha blockers and dutasteride. Alpha-blockers are used to treat a range of conditions, including high blood pressure and BPH.

Among U.S. men, prostate cancer is the second most deadly cancer after lung cancer. About 192,000 cases are diagnosed annually and some 27,300 die of the disease, according to the American Cancer Society.

Editor’s note: Andriole is a consultant for GlaxoSmithKline.

Source: New England Journal of Medicine, April 1, 2010

Now, health care providers will be able to gain applied training early in their medical education and careers with new simulation technology developed at the University of Virginia that will allow them to experience numerous scenarios that simulate prostate cancer.

The interactive tool, developed at the University of Virginia,  is capable of simulating more than 100 malignancy scenarios. The simulator consists of an anatomical model with four different prostates that can be altered by the inflation and deflation of small water balloons inside. The simulator models a breadth of physiological conditions that might take years to encounter through traditional patient examinations, said Martin, who is also interim vice president and chief officer for diversity and equity.

The project’s goal was to create multiple conditions – situations that were reconfigurable on demand by the clinician, simulating graded stages of cancerous tumors and benign prostatic hyperplasia in a life-like model.

Reba Moyer Childress, assistant professor of nursing and an expert in simulation education, directs the School of Nursing’s Clinical Simulation Learning Center. “Collaboration has helped us develop a realistic and robust simulator for teaching students and practitioners. The simulator is user-friendly, accurate and representative of how an actual patient will present,” she said.

A distinguishing feature of the design is that it provides immediate feedback to participants – both the instructor and the health care professional in training. “It provides a situation where they can make mistakes and learn,” Gerling said.

Training begins with supervision, followed by unsupervised scenarios. As it provides a gradation of experience, the simulation builds confidence, Martin said.

Prostate cancer detection is increased by coupling the rectal exam with prostate specific antigen testing, he said. “Early detection is the key, and VPES trains students on early detection.”

Each year more than 200,000 cases of prostate cancer are diagnosed and about 30,000 men die from the disease. African-American men are twice as likely to get prostate cancer as white men. It’s the second leading cause of cancer deaths in American men, he said.

According to the American Cancer Society, the five-year survival rate is 100 percent for patients whose prostate cancer is discovered early.

Gregory Gerling, assistant professor of systems and information engineering, along with  engineering graduate students, is working to produce a number of the simulators to be used in labs in the Nursing School and the new Claude Moore Medical Education Building.

The project is ongoing and will include refinements of the simulator and curricular initiatives are being developed in nursing and medicine to use the new technology.

The U.Va. Patent Foundation has licensed this technology to health care product supplier NASCO International Inc.

“We are delighted that we were able to help move this innovative simulator to the marketplace, where it will fulfill a critical need for enhanced training of medical professionals in detecting prostate cancer,” said Miette H. Michie, executive director and CEO of the U.Va. Patent Foundation. “This project is an excellent example of the many U.Va. discoveries that are making a positive impact on patients’ lives.”

The simulator project began in 2006 with $50,000 from the Academy of Distinguished Educators in the School of Medicine. Additional funding includes a $390,000 grant from the Congressionally Directed Medical Research Program.

Gerling and engineering graduate students worked on all aspects of project, creating the electronics and software, developing the soft silicon of the torso model that replicates human tissue and refining the techniques for making the balloons work.

Former graduate student Sarah Rigsbee, now at the Johns Hopkins Applied Physics Lab, built the first version of the simulator, and Nighuan “Miki” Wang, now at Microsoft, applied her research to the quantification of finger palpation techniques. Isabelle Rivest built the second user interface, and Angela Lee produced the second-generation version, which includes computerized adaptive testing algorithms that allow the simulator to evaluate the user’s responses.

Dr. Marcus Martin, professor of emergency medicine, and Childress lent their expertise in clinical and medical aspects related to prostate exams, education experience for nursing and medical students, residents and attending urologists and what is desired in teaching medical and nurse practitioners.

The collaborators also called on the expertise of urologists Drs. Dan Theodoresco and Tracey Krupski, prostate cancer experts, to help with development of the synthetic prostate tissue.

Nursing and medical students joined the research study team, providing feedback on skill development aspects of the training device at every level of the project.

“There’s truly an art to collaboration,” Childress said. “We learn each other’s roles to understand each discipline’s perspectives. It takes many disciplines to create a simulator.”

Source: University of Virginia, March 29, 2010

Skp2 is involved in promoting cell cycle regulation, cell proliferation, cell growth and the formation of tumors, and it is overexpressed in a variety of human cancers, according to lead author Hui-Kuan Lin, Ph.D., an assistant professor in M. D. Anderson’s Department of Molecular and Cellular Oncology.

Lin and colleagues found that inactivating Skp2 after oncogenes are overexpressed stifles cancer growth by causing senescence – the irreversible loss of a cell’s ability to divide and grow. Harnessing the power of cellular senescence to push rapidly dividing cells into a dormant state might provide another way to prevent or control common malignancies like prostate cancer.

Experiments Yield Surprising Results
The researchers conducted a series of experiments in tumor cell lines and mouse models that have shed new light on the interplay of Skp2 and cellular senescence.

“We discovered that Skp2 actually exhibits oncogenic activity, which is required for cancer development in multiple tumor models, such as the Pten-deficient and the p19Arf -deficient mouse models,” Lin said. “We found that Skp2 regulates tumorigenesis to trigger the cellular senescence program. This program is unexpectedly independent of the p19Arf-p53 pathway, which was previously believed to be critical for cellular senescence.”

The researchers also found that induction of cellular senescence did not cause DNA damage, and their results suggest that Skp2 inactivation can suppress cellular transformation to cancer even in the setting of an impaired p19Arf-p53 senescence response.

Moreover, research conducted in mouse models with faulty or inactive tumor suppressor networks showed that Skp2 deficiency and oncogenic signaling elicit a senescence response that restricts formation of tumors.

Novel Findings Point to New Therapeutic Approaches
Lin said these studies suggest that in the future Skp2 might be an effective therapeutic target for tumors with deregulated Akt signaling due to the loss or inactivation of Pten functions. Pten, which is commonly lost in human cancers, acts as a tumor suppressor gene by suppressing Akt signaling. Skp2 and Pten loss are believed to cooperate in triggering cellular senescence to restrict invasive prostate cancer.

“We now want to examine whether Skp2 is required in other tumor model systems, such as a HER2 model, to determine whether it is globally required for an oncogenic event,” said Lin, who previously was affiliated with Memorial Sloan-Kettering Cancer Center’s Department of Pathology and Cancer Biology and Genetics program and continued his research at M. D. Anderson. “We are testing whether Skp2 might be widely used for different types of cancer or perhaps used to trigger this newly described cellular senescence program.”

The researchers also are working to develop a Skp2-specific small molecule inhibitor to establish that the protein is indeed an important therapeutic target in cancer treatment. They believe that Skp2-based therapy might also be used as a general cancer treatment that could be combined with existing cancer therapies.

Source: University of Texas M. D. Anderson Cancer Center, March 17, 2010

The procedure used to diagnose prostate cancer (prostate biopsy) may cause harmful side effects, including bleeding and infection. Prostate cancer treatments, such as surgery and radiation therapy, may cause incontinence (inability to control urine flow), erectile dysfunction (erections inadequate for intercourse), and other complications. For these reasons, it is important that the benefits and risks of diagnostic procedures and treatment be taken into account when considering whether to undertake prostate cancer screening.

Source: National Cancer Institute

The PSA test and DRE are being evaluated to determine whether yearly screening to detect prostate cancer will decrease a man’s chances of dying from this disease.

Initial results from the trial showed that annual PSA testing for 6 years and annual DRE testing for 4 years (performed in the same years as the first four PSA tests) did not reduce the number of deaths from prostate cancer through a median follow-up period of 11.5 years (range 7.2 to 14.8 years). At 7 years of follow-up, a point in time when follow-up of the participants was essentially complete, 23 percent more cancers had been diagnosed in the screening group than in the control group. In the control group, men were randomly assigned to “usual care.”

These results suggest that many men were diagnosed with, and treated for, cancers that would not have been detected in their lifetime without screening and, as a consequence, were exposed to the potential harms of unnecessary treatments, such as surgery and radiation therapy. Nevertheless, it remains possible that a small benefit from the earlier detection of these “excess” cancers could emerge with longer follow-up. Follow-up of the PLCO participants will continue, therefore, until all participants have been followed for at least 13 years.

In contrast, initial results from another large randomized, controlled trial of prostate cancer screening, called the European Randomized Study of Screening for Prostate Cancer (ERSPC), found a 20 percent reduction in prostate cancer deaths associated with PSA testing every 4 years. At the time the results were reported, the participants had been followed for a median of 9 years.

The average number of PSA tests per participant in ERSPC was 2.1. Most participating centers in this study used a lower PSA cutoff value as an indicator of abnormality than was used in the PLCO trial (3.0 ng/mL versus 4.0 ng/mL). As in the PLCO trial, many more cancers were diagnosed in the screening group than in the control group. The ERSPC researchers estimated that 1,410 men would have to be screened and 48 additional cancers would have to be detected to prevent one death from prostate cancer.

Scientists are also researching ways to improve the PSA test, hopefully to allow cancerous and benign conditions, as well as slow-growing cancers and fast-growing, potentially lethal cancers, to be distinguished from one another. Some of the methods being studied include the following:

• PSA velocity: PSA velocity is the change in PSA level over time. A sharp rise in the PSA level raises the suspicion of cancer and may indicate a fast-growing cancer. A 2006 study found that men who had a PSA velocity above 0.35 ng/mL per year had a higher relative risk of dying from prostate cancer than men who had a PSA velocity less than 0.35 ng/mL per year. More studies are needed to determine if a high PSA velocity more accurately detects prostate cancer early.
• PSA density: PSA density considers the relationship between the level of PSA and the size of the prostate. In other words, an elevated PSA level might not arouse suspicion if a man has a very enlarged prostate. The use of PSA density to interpret PSA results is controversial because cancer might be overlooked in a man with an enlarged prostate.
• Free versus attached PSA: PSA circulates in the blood in two forms: Free or attached to a protein molecule. The free PSA test is more often used for men who have higher PSA values. Free PSA may help tell what kind of prostate problem a man has. With benign prostate conditions (such as BPH), there is more free PSA, while cancer produces more of the attached form. If a man’s attached PSA level is high but his free PSA level is not, the presence of cancer is more likely. In this case, more testing, such as a prostate biopsy, may be done. Researchers are exploring additional ways of measuring PSA and comparing these measurements to determine whether cancer is present.
• Alteration of PSA cutoff level: Some researchers have suggested lowering the cutoff levels used to determine whether a PSA measurement is normal or elevated. For example, a number of studies have used cutoff levels of 2.5 or 3.0 ng/mL (rather than 4.0 ng/mL). In such studies, PSA measurements above 2.5 or 3.0 ng/mL are considered elevated. Researchers hope that using these lower cutoff levels will increase the chance of detecting prostate cancer; however, this method may also increase overdiagnosis and false-positive test results and lead to unnecessary medical procedures. (See ERSPC trial results above.)

Source: National Cancer Institute

False-positive test results (also called false positives) occur when the PSA level is elevated but no cancer is actually present. False positives may lead to additional medical procedures that have potential risks and significant financial costs and can create anxiety for the patient and his family. Most men with an elevated PSA test result turn out not to have cancer; only 25 to 35 percent of men who have a biopsy due to an elevated PSA level actually have prostate cancer.

False-negative tests: False-negative test results (also called false negatives) occur when the PSA level is in the normal range even though prostate cancer is actually present. Most prostate cancers are slow-growing and may exist for decades before they are large enough to cause symptoms. Subsequent PSA tests may indicate a problem before the disease progresses significantly.

Source: National Cancer Institute

According to the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology for Prostate Cancer, additional treatment may be indicated based on the following PSA test results:

• For men who have been in the watchful waiting phase—their PSA level has doubled in fewer than 3 years or they have a PSA velocity (change in PSA level over time) of greater than 0.75 ng/mL per year, or they have a prostate biopsy showing evidence of worsening cancer.
• For men who have had a radical prostatectomy (removal of the prostate gland)—their PSA level does not fall below the limits of detection after surgery or they have a detectable PSA level (> 0.3 ng/mL) that increases on two or more subsequent measurements after having no detectable PSA.
• For men who have had other initial therapy, such as radiation therapy with or without hormonal therapy—their PSA level has risen by 2 ng/mL or more after having no detectable PSA or a very low PSA level.

Please note that these are general guidelines. Prostate cancer is a complex disease and many variables need to be considered by each patient and his doctor.

Source: National Cancer Institute

If no symptoms to suggest cancer are present, the doctor may recommend repeating DRE and PSA tests regularly to watch for any changes. If a man’s PSA level has been increasing or if a suspicious lump is detected during a DRE, the doctor may recommend other tests to determine if there is cancer or another problem in the prostate. A urine test may be used to detect a urinary tract infection or blood in the urine. The doctor may recommend imaging tests, such as a transrectal ultrasound (a test in which high-frequency sound waves are used to obtain images of the rectum and nearby structures, including the prostate), x-rays, or cystoscopy (a procedure in which a doctor looks into the urethra and the bladder through a thin, lighted tube that is inserted through the end of the penis; this can help determine whether urinary blockage is caused by an enlarged prostate). Medicine or surgery may be recommended if the problem is BPH or an infection.

If cancer is suspected, a biopsy is needed to determine whether cancer is present in the prostate. During a biopsy, samples of prostate tissue are removed, usually with a needle, and viewed under a microscope. The doctor may use ultrasound to view the prostate during the biopsy, but ultrasound cannot be used alone to tell if cancer is present.

Source: National Cancer Institute

Thus, there is no specific normal or abnormal PSA level. In addition, various factors, such as inflammation (e.g., prostatitis), can cause a man’s PSA level to fluctuate. It is also common for PSA values to vary somewhat from laboratory to laboratory. Consequently, one abnormal PSA test result does not necessarily indicate the need for a prostate biopsy. In general, however, the higher a man’s PSA level, the more likely it is that cancer is present. Furthermore, if a man’s PSA level continues to rise over time, other tests may be needed.

Because PSA levels tend to increase with age, the use of age-specific PSA reference ranges has been suggested as a way of increasing the accuracy of PSA tests. However, age-specific reference ranges have not been generally favored because their use may lead to missing or delaying the detection of prostate cancer in as many as 20 percent of men in their 60s and 60 percent of men in their 70s. Another complicating factor is that studies to establish the normal range of PSA values have been conducted primarily in white men. Although expert opinions vary, there is no clear consensus on the optimal PSA threshold for recommending a prostate biopsy for men of any racial or ethnic group.

Source: National Cancer Institute

Although specific recommendations regarding PSA screening vary, there is general agreement that men should be informed about the potential risks and benefits of PSA screening before being tested. Currently, Medicare provides coverage for an annual PSA test for all men age 50 and older.

Several risk factors increase a man’s chances of developing prostate cancer. These factors may be taken into consideration when a doctor recommends screening. Age is the most common risk factor, with nearly 63 percent of prostate cancer cases occurring in men age 65 and older. Other risk factors for prostate cancer include family history, race, and possibly diet.

Men who have a father or brother with prostate cancer have a greater chance of developing prostate cancer. African American men have the highest rate of prostate cancer, while Asian and Native American men have the lowest rates. In addition, there is some evidence that a diet higher in fat, especially animal fat, may increase the risk of prostate cancer.

Source: National Cancer Institute