The draft recommendation, by the United States Preventive Services Task Force and due for official release next week, is based on the results of five well-controlled clinical trials and could substantially change the care given to men 50 and older.

Read more, via NYT.com

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

Michael Diefenbach, Ph.D., Associate Professor of Urology at Mount Sinai School of Medicine developed a multimedia software program designed to help prostate cancer patients and their families make treatment decisions. The Cancer Information Service Research Consortium (CISRC) is supporting the study by providing the software to a group of patients in the study to learn if having a multimedia resource helps them determine their treatment pathway.

A diagnosis of prostate cancer can be overwhelming, and having to choose which treatment option is best for the patient is even more challenging. There are numerous options available with positive long-term treatment outcomes and patients typically desire therapy that will have the least impact on their quality of life.

“Having a discussion about treatment options is difficult for a patient who is still absorbing the shock of their diagnosis,” says Dr. Diefenbach. “We hope that providing this multimedia software will help patients and their families be fully engaged in their treatment discussions and make an informed decision with their doctor.”

The multimedia program includes interviews with leading prostate cancer experts and survivors, a discussion of the available treatment options, and a virtual notebook so patients can keep track of which elements of treatment are important to them.

The National Cancer Institute (NCI) provided funding for the CISRC study. Dr. Diefenbach’s team hopes to recruit 800 participants. Patients will be divided into two groups and each group will receive a packet of information regarding their diagnosis. One group will receive the free, multimedia program created by Dr. Diefenbach and printed material, and the other will receive printed material only.

“This study is designed to empower patients to take charge of their diagnosis and find the most suitable option for themselves,” continued Dr. Diefenbach. “Not only can the multimedia program help patients and their family members who enroll, their participation will help those who are diagnosed in the future.”

Patients interested in participating should call toll-free (866) 258-7981 to learn more.

Patients will be interviewed briefly before receiving further information. A follow-up interview will take place several months later. Those not qualifying for the study will be directed to other resources to help them with their questions. To be eligible to participate, the patient must have a recent diagnosis of prostate cancer and not have chosen any treatment.

Source: Mount Sinai Medical Center, March 11, 2010

For most of the nearly 200,000 American men diagnosed with prostate cancer each year, the disease is localized (i.e., has not yet spread), according to background information in the article. Treatment options for these men include surgery to remove the prostate and surrounding tissue (radical prostatectomy), radiation treatment, hormone therapy (including primary androgen deprivation therapy) or watchful waiting (expectant management). “Selecting the appropriate treatment can be challenging, since no therapy has emerged as clearly superior,” the authors write. “Patients rely on the clinical judgment, treatment philosophy and recommendations of counseling physicians to help them make informed decisions.”

Clinicians’ perceptions regarding optimal prostate cancer therapy appear to vary by specialty and geographic region. To assess whether these preferences were associated with treatment decisions, Thomas L. Jang, M.D., M.P.H., then of Memorial-Sloan Kettering Cancer Center, New York, and now of The Cancer Institute of New Jersey, New Brunswick, and colleagues identified 85,088 Medicare beneficiaries age 65 or older who were diagnosed with prostate cancer between 1994 and 2002.

Overall, 42,309 men (50 percent) were seen only by urologists, 37,540 (44 percent) by urologists and radiation oncologists, 2,329 (3 percent) by urologists and medical oncologists and 2,910 (3 percent) by all three specialists. Within nine months of diagnosis, 21 percent (18,201) had a radical prostatectomy, 42 percent (35,925) received radiation therapy, 17 percent (14,021) underwent primary androgen deprivation therapy and 20 percent (16,941) chose watchful waiting.

The type of treatment was strongly associated with the type of specialist consulted. Thirty-four percent of men who were seen exclusively by a urologist had a radical prostatectomy; it was the most frequent form of therapy in men 65 to 74 years who were seen only by urologists. In contrast, radiation therapy was the most common treatment for men of all ages who saw both radiation oncologists and urologists. Those seen by urologists, with or without medical oncologists, were more likely than those evaluated by urologists and radiation oncologists to receive primary androgen deprivation therapy or watchful waiting.

Visits to primary care physicians were infrequent between the time a man was diagnosed and when he started treatment; 22 percent of patients visited any primary care clinician during this timeframe, and 17 percent visited a primary care clinician with whom he had an established relationship. Regardless of age, co-occurring illnesses or specialist visits, men who saw primary care clinicians were more likely to be treated with watchful waiting.

“Our findings provide new insight into the relationship between physician visit patterns and receipt of therapy for localized prostate cancer,” the authors write. “Prior physician surveys suggest that urologists and radiation oncologists might recommend their own treatment modality based on their stated preferences in response to hypothetical survey questions. The pattern of specialist visits and treatment that we observed suggests that these preferences may be affecting treatment decisions of Medicare patients.”

“This finding and the known preferences of prostate cancer specialists for the treatment they themselves deliver underscores the need to ensure that all men are well informed and have access to balanced information prior to making this important treatment decision,” they conclude

This study was funded by a National Institutes of Health Ruth Kirchstein National Research Service Award and grants from the National Cancer Institute. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support.

Source: Arch Intern Med. 2010;170[5]:440-450, March 8, 2010

The respiratory, enteric, orphan virus (commonly known as reovirus) is a non-attenuated, environmental virus that has shown oncolytic potential against many types of cancer, specifically lymphoid, ovarian, breast, pancreatic and high grade glioma cancer, according to the study. This is the first time the virus has been studied against prostate cancer.

“The reovirus is a very common, ubiquitous virus that most people are exposed to. As far as we know, it doesn’t cause any significant illness in humans, even though when someone is exposed to it, it manifests, at most, as a mild respiratory infection or mild diarrhea,” said researcher Don Morris, M.D., Ph.D., medical oncologist in the Department of Oncology at the Tom Baker Cancer Center in Alberta, Canada.

“For the treatment of localized prostate cancer, we found that the reovirus is safe and has evidence of specific tumor vs. normal prostate cell efficacy,” added Morris.

Using preclinical and clinical settings, Morris and colleagues examined the efficacy of the reovirus as an experimental therapeutic for prostate cancer in vitro and in vivo. Among the six patients who participated in the study, all had early-stage, organ-confined prostate cancer. Each patient underwent a single intralesional virus injection into a suitable prostate cancer nodule via transrectal ultrasound guidance. Three weeks later, Morris and colleagues removed the prostate as part of the patient’s standard treatment for correlative science analysis.

Findings showed safety and efficacy with minimal toxicity and no viral replication in the normal parts of the prostate, according to Morris. Cancer cell death was evident in the prostate. Studies to date have suggested that the virus’ side effects are relatively modest, consisting of mild, self-limiting, flu-like symptoms.

“Our results are a stepping stone into future prostate cancer clinical trials with another category of cancer therapeutics,” he said.

Robert Clarke, Ph.D., D.Sc., professor of oncology at Lombardi Comprehensive Cancer Center at Georgetown University and an editorial board member of Cancer Research, agreed, stating that he believes this study is worthy of subsequent clinical trials of the reovirus as a possible way of treating some prostate cancers.

“People have known of this application of the reovirus in trials, but no one to my knowledge has conducted studies in prostate cancer,” said Clarke, who was not associated with this study. “I think this is an interesting approach. There is not a lot done in oncolytics, but clearly it is an area that is getting increasing attention, and we need everything we can get our hands on to make a difference in these patients.”

Funding for this research was provided by the Alberta Cancer Foundation, Oncolytics Biotech Inc. and the Prostate Cancer Research Foundation of Canada.

Source: Cancer Research, March, 2010