Treatment of localized prostate cancer is controversial because, for some, this disease will not progress during their life time, and treatment may incur serious and long-lasting side effects. An increasingly popular option is active surveillance, or deferring treatment until evidence of disease progression.

To investigate outcomes of patients treated with active surveillance, Pär Stattin, M.D., of the Department of Surgical and Perioperative Science at Umea University, and colleagues conducted an observational study of 6849 patients in the National Prostate Cancer Register of Sweden with localized prostate cancer who were 70 years old or younger. The patients had low or intermediate risk of prostate cancer progression and were treated with active surveillance or watchful waiting; or radical prostatectomy or radiation therapy from 1997 through December 2002.

In this cohort, 2021 patients received surveillance, 3399 received radical prostatectomy, and 1429 received radiation therapy. After a median follow-up of 8.2 years, there were 413 deaths in the surveillance group; 286 in the radical prostatectomy group, and 1429 patients in the radiation therapy group. The researchers found a much higher percentage of death from competing causes in the surveillance group (19.2%, compared with 6.8% in the prostatectomy group and 10.9% in the radiation therapy group), suggesting that patients with a shorter life expectancy were more often selected for surveillance than surgery or radiation therapy.

This observational study found that the risk of calculated cumulative prostate cancer-specific death was lower among patients in the prostatectomy group than those in the surveillance group. However, the difference in absolute risk between the groups was modest, at 1.2%, after 10 years of follow-up.

The authors conclude that surveillance is the best strategy for many patients with low-risk prostate cancer. “With a 10-year prostate cancer-specific mortality of less than 3% for patients with low-risk prostate cancer on surveillance, this strategy appears to be suitable for many of these men,” they write.

In an accompanying editorial, Siu-Long Yao and Grace Lu-Yao of The Cancer Institute of New Jersey write that perhaps the most remarkable result of this and other recent studies is that survival among most patients with localized disease managed conservatively is now similar to that of control subjects of similar ages.

Indeed, most men will die of another disease, and a prostate cancer diagnosis should act as a wake-up call for men to take charge of their healthcare and take better care of themselves. However, the authors write that a significant challenge is that, “A bevy of cancer research has demonstrated that cancer patients are particularly receptive to health-care advice after diagnosis, although older men, like those with prostate cancer, appear to be less receptive to change.”

Source: Kristine Crane, Journal of the National Cancer Institute

The health of the prostate has long been considered dependent on the level of the male hormones collectively known as androgens however, it is now recognized that estrogens and their metabolites (estrogen broken down by chemical processes in the body) play a role in its normal growth as well as in prostate cancer.

“The aim of our study was to evaluate the use of estrogen metabolites, as a marker for prostate cancer risk,” says Ourania Kosti, PhD, at Georgetown Lombardi Comprehensive Cancer Center.

For the study, the researchers measured estrogens and their metabolites in the urine collected from 77 men with prostate cancer, 77 healthy controls and 37 men that underwent biopsy and but were diagnosed cancer-free.

The relative amounts of the 15 estrogens and estrogen metabolites in the urine of prostate cancer cases were similar to that of non-cancer patients with the exception of the estrogen metabolite 4-OHE1.

“This particular estrogen metabolite appeared to be more abundant among men diagnosed with prostate cancer,” explains Kosti.

Kosti says her team also observed that the estrogen metabolites considered as ‘harmful’ estrogens in breast cancer (16-KE2 and 17-epiE3) are secreted in higher amounts among those without prostate cancer and in lower amounts in those with prostate cancer.

“This suggests that these particular estrogens may have a protective role against prostate cancer development,” explains Kosti. “It is possible that different tissues respond to estrogens different ways, therefore the potential role of 16-KE2 and 17-epiE3 in prostate cancer prevention and management should be further explored.”

Source: Karen Mallet, Georgetown University Medical Center via EurekAlert

According to the findings of the Phase 1-2 study, MDV3100 not only shrank patients’ tumors, but also reduced serum levels of the tumor marker prostate-specific antigen (PSA), stabilized disease that had spread to soft tissues and the bone, and reduced the number of circulating tumor cells in the blood.

“We were encouraged to see antitumor activity in men whose disease had spread to other parts of the body after either becoming resistant to previous hormone treatments or progressing following chemotherapy,” said the study’s lead author Howard Scher, MD, Chief of the Genitourinary Oncology Service at Memorial Sloan-Kettering. “These findings strengthen the drug’s potential to change the outlook for a group of patients who currently have limited effective treatment options from which to choose.”

According to the research, MDV3100 slows tumor growth and induces tumor cells to die in men with CRPC, or hormone-refractory disease, which depends on male hormones to grow, but is unresponsive or becomes resistant to standard therapies used to lower or block those hormones. MDV3100 works by blocking testosterone from binding to the androgen (male hormone) receptor, stopping the movement of the androgen receptor to the nucleus of prostate cancer cells, preventing the receptor from binding to DNA, and inducing cancer cell death, even when the expression of the androgen receptor is elevated.

“This study validates what our preclinical studies have suggested: that sustained androgen receptor signaling drives CRPC and that a substantial number of CRPC tumors that progress despite multiple hormone and chemotherapy treatments remain dependent on androgen receptor signaling for growth,” said study co-author, Charles Sawyers, MD, Chair of Memorial Sloan-Kettering’s Human Oncology and Pathogenesis Program and a Howard Hughes Medical Institute investigator.

The drug was co-invented by Dr. Sawyers and Michael Jung, PhD, Professor of Chemistry at the University of California, Los Angeles. Their research originally demonstrated that CRPC cells have increased expression of the androgen receptor and that elevated expression of this receptor may contribute to disease progression due to a developed resistance to hormone treatment. Their collaboration led to the discovery of a number of nonsteroidal, small molecule antiandrogen compounds, including MDV3100.

In the current study, 140 patients were treated with doses of MDV3100 ranging from 30 to 600 mg daily. PET imaging, bones scans, and blood tests were used to assess the antitumor effects of the drug, which were observed at all dosages. Investigators reported declines in PSA of at least 50 percent in more than half of the patients and tumor regressions in 22 percent of the patients. Overall, two-thirds of patients had partial remissions or stable disease in tumors that had spread to soft tissue or bone.

The findings also showed that the number of circulating tumor cells fell in 49 percent of patients, and 91 percent of patients who initiated therapy with favorable counts retained favorable counts during treatment. This is important because previous research shows that changes in circulating tumor cell counts after treatment were more predictive of survival than were changes in PSA, with favorable post-treatment counts associated with a 21-month median survival.

The drug was generally well tolerated, with nausea, constipation, diarrhea, and anorexia being the most common mild side effects reported. The most frequently reported Grade 3 side effect at higher doses was fatigue. The researchers determined that the maximum tolerated dose for sustained treatment was 240 mg daily.

Based on the positive results of the current study, a multinational randomized Phase 3 clinical trial has begun to examine MDV3100 versus a placebo for the treatment of men with advanced prostate cancer who were previously treated with chemotherapy. Information about patient eligibility and enrollment can be obtained by visiting www.affirmtrial.com or by calling the AFFIRM study’s toll free hotline at 888-782-3256.

Source: Jeanne D’Agostino, Memorial Sloan-Kettering Cancer Center

The recently discovered retrovirus, xenotropic murine leukemia virus-related virus (XMRV), has been identified in some prostate cancer patients. In light of conflicting data concerning XMRV, standardized diagnostic testing is important to identify patients in which XMRV is present and to determine whether it plays a role in the incidence of prostate cancer. An article published in the April issue of Urology® is a step in this direction as researchers from Emory University report the successful development of an experimental clinical test for XMRV.

“We cannot as a scientific community begin to answer the basic questions of XMRV transmission, frequency in the population, association with disease, etc. until we can effectively test for infection,” according to lead investigator John A. Petros, MD, Associate Professor of Urology, Emory University School of Medicine and Veterans Administration Hospital.

Dr. Petros and co-investigators adapted technology developed in the HIV arena (neutralizing antibody assay) and have developed a serum test that can identify patients who have previously been infected with the virus. This assay has been rigorously confirmed by two independent labs and two independent technologies (PCR and FISH), thus confidence in the accuracy of the test is high.

The mode of transmission of the virus is unknown. No method is available to screen either blood or tissue donors for infection and no data are available regarding whether the virus can be transmitted by blood transfusion or tissue transplantation. Dr. Petros comments, “The public deserves to know if the next blood transfusion or organ donation will give them XMRV retrovirus, an infection which lasts for life, and could possibly be related to prostate cancer. The failure to develop accurate tests for this virus is a serious public health oversight.”

Although the assay used in the present report involved the inhibition of infection of target cells by viral-like particles with the XMRV envelope protein expressed on their surface, results also suggest that more standard serologic tests for antibodies against specific viral antigens can be developed in the future.

The authors conclude that “our report adds to the growing body of evidence that XMRV is indeed a novel gamma-retrovirus capable of infecting humans and that at least some patients with prostate cancer have been infected with XMRV. We have reported serologic evidence of infection and that the serology correlated with tissue-based assays. The concordance of 3 independent methods of detecting infection added confidence to the assertion that this recently discovered virus is real and possibly related to human disease. Robust clinical assays are needed to detect XMRV infection, and much work remains to be done in determining whether XMRV is indeed an oncogenic virus or simply an associated epiphenomenon.”

Source: Sarah Kane, Elsevier Health Sciences

Research focusing on the number of children a man has have pointed to male fertility’s potential associated with risk for prostate cancer. However, studies on the topic have generated conflicting results: some have found that men with children had a higher risk than childless men; some have found that men with fewer children had a higher risk than men with more children; still others failed to identify any association between the number of children fathered and a man’s risk for prostate cancer.

Because the number of children a man has may not accurately reflect his ability to cause a pregnancy, Thomas Walsh, MD, MS, of the University of Washington in Seattle and his colleagues designed a more accurate study to evaluate the association between male infertility and prostate cancer. They studied the risk for prostate cancer in a group of 22,562 men evaluated for infertility from 1967 to 1998 in 15 California infertility centers. The incidence of prostate cancer in these men was compared with the incidence in a sample of men in the general population who were of similar ages and from similar geographic locations.

The researchers identified 168 cases of prostate cancer that developed in men who were evaluated for infertility. That number not significantly different from the expected rate (185 cases), suggesting that overall, men evaluated for infertility were not at a higher risk of being diagnosed with any type of prostate cancer compared with men in the general population. However, men who were evaluated and found to be infertile were 2.6 times more likely to be diagnosed with high grade prostate cancer than men who were evaluated but were found not to be infertile.

The authors say if these results are confirmed in other studies, it may be appropriate for infertile men to be considered for early prostate cancer screening, given their elevated risk for aggressive disease. They add that the results should stimulate research on possible common biological pathways underlying infertility and prostate cancer.

Source: David Sampson, American Cancer Society

Boosting the radiation dose given to prostate cancer patients to a level that cut tumor recurrence in half did not increase the severity of side effects reported by patients up to a decade later. The study led by Massachusetts General Hospital (MGH) Cancer Center researchers also found that patients characterized the impact of continuing side effects on their quality of life as considerably less bothersome than would be expected, based on earlier studies. The article appears in the March 17 cancer issue of the Journal of the American Medical Association.

“A surprising number of men who reported symptoms that had bothered other patients surveyed before or soon after prostate cancer treatment described their current symptoms as normal,” says James Talcott, MD, SM, of the Center for Outcomes Research at the MGH Cancer Center, who led the study. “If this result is seen in other groups, it may alter how we describe the long-term impact that patients should expect on their quality of life.”

The current study is based on a survey of participants in trial conducted in the late 1990s at MGH and at the Loma Linda University Medical Center in California. That study compared the results of two different radiation doses for treatment of early-state prostate cancer. All participants received an equal dose of conventional X-ray therapy and a booster dose of proton therapy that brought the total dose to either the then-standard level of 70 Gy or to 79 Gy, which is now the usual dosage for similar tumors. Proton therapy reduces the amount of radiation delivered to normal tissues in front of and behind a tumor, and the X-ray therapy was also given in a way to minimize the irradiation of normal tissues.

The earlier study showed that, five years after treatment, the higher radiation dose had reduced tumor recurrence by about half, a benefit that persisted up to nine years after treatment. Participants’ physicians reported similarly low rates of treatment-related toxicity in both groups, but the patients themselves had not been asked about their post-treatment experiences.

The current investigation was designed to study participants’ reports of their experiences, considered to be the most accurate measure of side effects. The researchers sent all surviving participants a questionnaire that included standardized assessments of the urinary, bowel and sexual symptoms usually affected by prostate cancer treatment. Separate from the specific symptom assessment, participants were asked to rank their function in those areas as normal, intermediate or poor. They also were surveyed about their attitudes regarding their current health, their cancer and the treatment decisions they had made.

Survey questionnaires were returned by 280 of the original 398 study participants, evenly divided between the standard- and high-dose groups. Both groups reported similarly low levels of treatment side effects and quality of life problems. Patients in the standard-dose group – who had greater incidence of tumor recurrence, often requiring additional therapies – expressed less confidence that their tumors were under control and more regret about their treatment choice, which in this case was to enroll in the randomized trial. Participants’ overall ranking of the urinary, bowel and sexual functions was often better that would be expected based on the symptoms they reported.

“The assessment we used includes scales that ask patients how bothered or distressed they are by each symptom,” Talcott explains. “In earlier work, Wwe matched reported the symptom levels they reported to how much those symptoms had bothered other patients we surveyed before or soon after treatment in previous studies. If no symptoms were at a level that caused distress, that function would be considered normal. If a patient reported one symptom that usually caused high levels of distress, that function would be ranked as poor. Everyone else – those who reported any moderately distressing symptoms but no highly distressing ones – was ranked as intermediate.”

More than half of the participants in the current study whose function would be categorized as intermediate actually ranked that function as normal. Similarly about 20 percent of those who would be categorized as poor in terms of urinary irritation or obstruction ranked that function as normal, as did around 40 percent of those rated poor for bowel problems.

“Symptoms that seem to bother other patients early in the course of their prostate cancer were regarded as normal by these patients nearly a decade after treatment,” Talcott says. “As clinicians, we know that patients adapt to their situation and accept physical changes as the ‘new normal.’ When talking with prostate cancer patients, I’ve been surprised when, for example, a patient in his late 60s who became impotent two or three years after treatment would comment, ‘Well, it would have happened anyway to a man my age.’

“While these results need to be confirmed, since this is just one study,” he continues, “it’s looking as if we should tell patients that treatment side effects probably will bother them less than they originally fear because they are likely to adjust and experience less distress over time. We also may need to rethink our standard measures of treatment outcomes, which assume that the impact of symptoms on patients’ quality of life does not change over time. While that may be true for pain, it doesn’t seem to be true for these sorts of symptoms.” Talcott is an associate professor of Medicine at Harvard Medical School.

Source: Sue McGreevey, Massachusetts General Hospital

“The American Cancer Society is a ‘false prophet’ when it comes to telling the truth about the effectiveness of the PSA test,” said ZERO’s CEO Skip Lockwood. “Dr. Otis Brawley disregards scientific data about the value of the PSA test in saving lives. In fact, his views at a recent medical conference were vigorously challenged by physicians and researchers in attendance.”

“Dr. Brawley seems more concerned about sex than saving lives. He’s obsessed with the side effects of treatment rather than a solution for saving lives. He wants you to trust him instead of the 30,000 urologists in the U.S. and gamble you’re not among the thousands of men who die each year with aggressive prostate cancer tumors,” said Lockwood.

Lockwood acknowledges that the PSA test, like the mammogram, is not perfect.

“No one disputes that the PSA test cannot distinguish slow-growing tumors from rapidly growing ones, yet no one disputes that the PSA test is still the best tool available for early diagnosis and prompt treatment for prostate cancer.

“The long-term solution is to discover a new biomarker for prostate cancer without false positives or negatives and one that determines who has a life-threatening disease and who doesn’t.

One of the nation’s leading experts on prostate cancer, Dr. William J. Catalona of Northwestern University, commented, “Although the PSA test is not perfect, it is effective in identifying men at high risk for prostate cancer and for detecting it early.”

The PSA test, the most prevalent method in use today for prostate cancer, has saved thousands of lives. The PSA test and advances in treatment have led to a 40 percent reduction in prostate cancer deaths since the mid-1990s, according to the National Cancer Institute. Because of the PSA test, 90 percent of all prostate cancers are now discovered before they spread outside the gland, according to the American Cancer Society’s own data.

Dr. Patrick C. Walsh, distinguished professor of urology at Johns Hopkins University noted, “Because prostate cancer produces no symptoms until it’s too far advanced to cure, as appropriate, men should have a PSA test and examination. Until an alternative exists, prostate cancer testing is the best option we have to allow men to make an informed decision.”

Despite misleading claims by the ACS, the value of early detection through PSA testing is supported by more than a dozen leading U.S. organizations.

These include the American Urological Association, National Comprehensive Cancer Network, Prostate Cancer Foundation, Prostate Cancer Research Institute, Malecare Prostate Cancer Support, Men’s Health Network, National Alliance of State Prostate Cancer Coalitions, Prostate Cancer International, Prostate Conditions Education Council, Prostate Health Education Network, The Prostate Net, Us TOO International Prostate Cancer Education and Support Network, and Women Against Prostate Cancer.

This is not the first time that the ACS has been sharply challenged. Claims that their views are based on “scientific evidence” were disputed as recently as late last year (and more recently, at the 2010 Genitourinary Cancers Symposium held last week).

ACS became embroiled in a firestorm of controversy last October by seeking to change its guidelines that women did not need an annual mammogram until age 50, instead of 40. ACS quickly backed off after an outcry from the public and health and government officials.

“The only difference between the PSA test and mammograms is there aren’t millions of men who will stand up to the claims being peddled by Brawley and the American Cancer Society,” Lockwood said.

Contrary to ACS claims, medical data suggest mammograms and PSA testing are effective. Based on data by the U.S. Preventive Services Task Force (USPSTF), mammography screening has led to a 15 percent reduction in breast cancer deaths. USPSTF also references an ongoing screening study where early detection (using the PSA test) has so far reduced prostate cancer deaths by 20 percent.

“This concerted agenda by ACS and Mr. Ablin, both in their timing and their message, purposely fails to disclose all of the facts about PSA testing. Mr. Ablin in particular should be pleased that his discovery of PSA has led to a 40 percent reduction in prostate cancer deaths.”

Similarities between breast and prostate cancer data in the U.S. are striking. Each is the most frequently diagnosed noncutaneous cancer and the second leading cause of cancer death for their respective gender. In 2009, new cases of each cancer were at about 194,000. One in six men is struck with prostate cancer annually; for breast cancer, it’s one in eight women.

Source: The Project to End Prostate Cancer

Many prostate cancer patients choose to take nutritional supplements to improve or increase sexual potency and alleviate symptoms associated with poor prostate health. Some studies show that about half of prostate cancer patients use an herbal or dietary supplement and most do so without discussing it with their doctor.

Researchers at William Beaumont Hospital in Royal Oak, Mich., sought to determine if three widely used commercial prostate-specific dietary supplements changed the radiosensitivity of normal prostate and/or androgen-positive and -negative prostate tumor cell lines. There have been published reports of negative clinical effects for some tumor sites from the use of certain dietary supplements after chemotherapy, but the effect of dietary supplements on radiation therapy treatments is not well-known.

The study authors found that the cell growth and radiosensitivity of the malignant tumor cells were not affected by any of the supplements, but two of the supplements inhibited the growth rate of the normal prostate cell lines while a third supplement also increased the cellular radiosensitivity of some normal cell lines by inhibiting DNA repair.

“Cancer patients turn to supplements to aid in their treatments for a variety of reasons, but this study proves that what some patients believe is helping them may actually be harming them,” Brian Marples, Ph.D., senior author of the study and a radiobiologist at William Beaumont Hospital and clinical research professor at Oakland University William Beaumont School of Medicine, said. “It is very important for all patients to discuss any type of supplement they may be taking with their physician and especially important for prostate cancer patients receiving radiation therapy as this study shows that it may be negatively affecting the effectiveness of their treatments.”

The findings, published in a recent issue of the journal European Urology, compared treatments for three groups of study participants with enlarged prostates over four years. The study, which included more than 4,800 men, is one of the first to compare single and combo medication regimens in such a large group.

The first group of study participants received the drug dutasteride; the second group received tamsulosin; and the third received a combination of the two medicines.

“We found the combination therapy to be superior at reducing risk of BPH progression,” said Dr. Claus Roehrborn, chairman of urology at UT Southwestern and lead author of the study. “The two medications joined forces in terms of symptom control. On the strengths of both dutasteride and tamsulosin, participants reported fewer symptoms, and we observed a 25 percent reduction in prostate volume.”

Dr. Roehrborn added that subjects who received the combination therapy also showed a 50 percent reduction of prostate-specific antigen (PSA), a protein produced by both cancerous and noncancerous prostate tissue. PSA levels can be an indication of increased risk of cancer because cancer cells usually make more PSA than do benign cells, causing PSA levels in the blood to rise. Should PSA levels continue to rise after beginning therapy, patients should be monitored closely because the combination medicines do lower PSA readings, Dr. Roehrborn said.

Enlarged prostate, also called benign prostatic hyperplasia (BPH), is a common urologic condition that affects about 50 percent of men between the ages of 51 and 60 and up to 90 percent of men over the age of 80.

Symptoms of the condition can be prolonged and severe. Prostate enlargement creates pressure on the urethra, making it difficult to urinate, which can lead to acute urinary retention. This retention causes a host of other problems, including extreme discomfort and infections.

Researchers also looked at the data to determine if the number of study participants needing surgery for BPH decreased with the combination medication regimen. Compared with tamsulosin alone, the combination of drugs reduced the incidence of acute urinary retention by 67 percent and reduced the need for BPH-related surgery by 70 percent.

“We found a 65 percent decrease in the relative risk of acute urinary retention or BPH-related surgery compared with tamsulosin alone and just over a 19 percent reduction compared with dutasteride alone,” said Dr. Roehrborn.

Those taking the combination of drugs also were less likely than those in the other two groups to discontinue therapy, he said. Participants themselves noted that the combo medicines were most effective at reducing symptoms.

“There is currently no combination drug for doctors to prescribe for these patients,” Dr. Roehrborn said. “This research should provide physicians better information when they decide on a course of treatment for patients with BPH.”

Other researchers contributing to the study were from the Deaconess Clinic in Evansville, Ind.; State University of Rio de Janeiro; Universita Vita Salute San Raffaele, Italy; University of Toronto; and GlaxoSmithKline.

The study was funded by GlaxoSmithKline. Dr. Roehrborn is a consultant to the pharmaceutical company.

Source: UT Southwestern Medical Center.

To study the risks men diagnosed with prostate cancer in the United States face, Fang Fang, M.D., of the Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, in Boston, and colleagues used data from over 340,000 prostate cancer patients listed in the Surveillance, Epidemiology, and End Results database between 1979 and 2004 and from the general population. The researchers compared risks in the first year and months after diagnosis.

According to the study, 148 men died of suicide (mortality rate = 0.5 per 1,000 person-years) and 6,845 died of cardiovascular diseases (mortality rate = 21.8 per 1000 person-years). Increased risk of suicide was found during the first year, in particular the first 3 months. The risk of cardiovascular death was slightly elevated during the first year, especially in the first month and particularly among those with metastatic disease.

According to the study, the elevated suicide risk was apparent before prostate-specific antigen (PSA) testing was common (1979-1986) and when it was first introduced (1987-1992), but not since PSA testing has been widespread (1993-2004). The authors say this observation is most likely due to the potentially lower degree of stress associated with the diagnosis of indolent prostate cancer.

“We believe that suicide and cardiovascular death reflect only the tip of the iceberg of anxiety, mood disturbance, and perhaps other mental illness (or suffering) after a prostate cancer diagnosis,” the authors write. “Hence, our study suggests the potential importance of providing emotional counseling and support for patients newly diagnosed with cancer. It also adds to the increasingly complex scenario of pros and cons of extensive PSA testing, which entails detection of large numbers of nonlethal prostate cancers.”

Source: Steve Graff, Journal of the National Cancer Institute