Common prostate cancer treatment associated with decreased survival in older men

A common prostate cancer therapy should not be used in men whose cancer has not spread beyond the prostate, according to a new study led by researchers at Henry Ford Hospital.

The findings are particularly important for men with longer life expectancies because the therapy exposes them to more adverse side effects, and it is associated with increased risk of death and deprives men of the opportunity for a cure by other methods.

The research study has been published online in European Urology.

The focus of the new study is androgen deprivation therapy (ADT), in which an injectable or implanted medication is used to disrupt the body's ability to make testosterone. ADT is known to have significant side effects such as heart disease, diabetes, increased weight gain and impotence; however a growing body of evidence suggests ADT may in fact lead to earlier death.

Since the 1940s, the therapy has been a mainstay of treatment for prostate cancer that has metastasized, or spread beyond the prostate gland. Still other studies support the use of ADT when it is used as an adjuvant, or in addition to, radiation therapy for higher risk prostate cancer. No evidence exists to support the exclusive use of ADT for low risk or localized prostate cancer.

"The use of ADT as the primary treatment for localized and low risk prostate cancer increased over time, despite known harmful side effects and a lack of data to support such use," says Jesse D. Sammon, D.O., a researcher at Henry Ford Hospital's Vattikuti Urology Institute and lead author of the new study. "In the 1990's it became exceedingly common to use ADT in place of radical prostatectomy or radiation therapy."
Concerns over the possible misuse of ADT alone in the treatment of prostate cancer, as well as a growing awareness of its potential damage, led to changes in Medicare reimbursement policies for ADT in 2004.

This resulted in a 40 percent drop in reimbursement, and a reduction in inappropriate use of ADT from 38.7 percent to 25.7 percent for newly diagnosed localized prostate cancers.

"At the same time, there was a growing awareness of ADT's many possible adverse effects, including decreased libido, anemia and fatigue, and a higher risk of metabolic and cardiovascular disease," Dr. Sammon says.

"In designing our study, we hypothesized that the adverse effects of ADT might be more pronounced in men with longer life expectancies since they would likely be treated with ADT for a longer period- and be exposed to more treatment-related side effects."

Drawing on data from nations largest cancer registry (SEER) (Surveillance, Epidemiology, and End Results) the researchers then linked to records from Medicare and identified 46,376 men diagnosed with localized prostate cancer who did not undergo radical prostatectomy or radiation therapy for prostate cancer, diagnosed between 1992-2009. Among them, 38.5 percent were treated with ADT.

Further statistical analysis confirmed the study's hypothesis, notes Dr. Sammon.

"No evidence supports the use of ADT in men with low risk, localized prostate cancer, while use of this therapy is decreasing over time it is still very common," he says

"We found that primary ADT is associated with decreased survival in men with localized prostate cancer relative to men who receive no active treatment, particularly in men with longer life expectancies. So we concluded that ADT should not be used as a primary treatment for men with prostate cancer that has not spread beyond the prostate or men with moderate to high risk disease undergoing radiation therapy."

PSA-testing and early treatment decreases risk of prostate cancer death

The study is based on data from nation-wide, population-based registers in Sweden including the Cancer Register, The Cause of Death Register and the National Prostate Cancer Register (NPCR) of Sweden.
“Our results show that prostate cancer mortality was 20 procent lower in counties with the highest incidence of prostate cancer, indicating an early and rapid uptake of PSA testing, compared with counties with a slow and late increase in PSA testing,” says Pär Stattin, lead investigator of the study.
“Since the difference in the number of men diagnosed with prostate cancer is related to how many men undergo PSA testing, we think our data shows that PSA testing and early treatment is related to a modest decrease in risk of prostate cancer death,” says Håkan Jonsson statistician and senior author of the study.
“In contrast to screening in randomized studies our data is based on unorganized, real life PSA testing. We therefore used a statistical method that excludes men that were diagnosed prior to the introduction of PSA testing since these men could not benefit from the effect of PSA testing,” continues Håkan Jonsson.
“The results in our study are very similar to those obtained in a large European randomized clinical study (ERSPC) thus confirming the effect of PSA testing on the risk of prostate cancer death. However, we have to bear in mind that the decrease in mortality is offset by overtreatment and side effects from early treatment. PSA testing sharply increases the risk of overtreatment, i.e. early treatment of cancers that would never have surfaced clinically. We also know that after surgery for prostate cancer most men have decreased erectile function and that a small group of men suffer from urinary incontinence. Our data pinpoints the need for refined methods for PSA testing and improved prostate cancer treatment strategies,” concludes dr Stattin.

Surgery may trump a "watch-and-wait" approach when it comes to treating prostate cancer, especially in younger patients

Surgery may trump a "watch-and-wait" approach when it comes to treating prostate cancer, especially in younger patients, according to a new study.

Death and the spread of cancer were less likely for men who underwent a radical prostatectomy to remove the prostate gland compared to those who didn't -- regardless of age, said study co-author Jennifer Rider, an assistant professor in the department of epidemiology at the Harvard School of Public Health.

"And when we looked at subgroups of age, we found the benefit really appeared to be limited to men with the longest life expectancy," she said.

For years, experts have debated how best to treat the disease -- either using a watch-and-wait approach or removing the gland to help reduce the cancer's spread and extend life.

Dr. Jim Hu, director of robotic and minimally invasive surgery in the urology department of the University of California, Los Angeles, said: "There has been considerable controversy in the United States about PSA [prostate specific antigen] screening for prostate cancer and treatment of prostate cancer."

Experts opposed to surgery say many tumors won't become life-threatening and can be monitored with tests from time to time.

The prostate is a small, walnut-shaped gland that sits below a man's bladder. It produces the fluid that nourishes and transports sperm. According to the American Cancer Association, about 233,000 men in the United States will be diagnosed this year with prostate cancer, which can be detected by a PSA test and by a physical exam.

The Harvard researchers, along with colleagues from Uppsala University Hospital in Sweden, used data from a large Scandinavian prostate cancer study to evaluate about 700 men with early prostate cancer to learn more about life expectancy with the disease.

The men were randomly assigned to either surgery or a watchful-waiting group that received no initial treatment. All were under age 75 and had a life expectancy of 10 or more years. The scientists followed them for up to 23 years, through 2012.

The researchers reported in the March 6 issue of the Journal of the American Medical Association that about 58 percent of the men in the surgery group and 71 percent of the men in the watchful-waiting group died during the study. Prostate cancer was the cause of 18 percent of deaths in the surgery group and about 28 percent in the watchful-waiting group.

Rider said it's important to note that the men in the study had not had their prostate cancer detected using a PSA test and that the data was collected between 1989 and 1999, when the primary form of detection involved a manual exam by the doctor.

"We know PSA screening advances a man's diagnosis by about five to 10 years," Rider said. "So a man today would have the disease diagnosed earlier in his life than in our study."

Hu said it's also key to keep in mind that prostate cancer is typically a slow-growing tumor.

"A lot of the benefit in treating prostate cancer isn't seen for years," Hu said. This study demonstrates that with a median follow-up of 13.4 years, eight men needed to undergo radical prostatectomy to save one from prostate cancer. That's when they saw the survival benefits for surgery versus watchful waiting. This number will continue to go down with longer follow-up."

Rider also said men over 65 who had surgery were less likely to have their cancer spread. "But we don't know if that translates to a mortality benefit," she said.

It was a nice study design, Hu said. "It shows there is a benefit to treating men with prostate cancer," he said.

But he said the findings differ from another recent study by the U.S. Veteran's Administration hospitals that demonstrated that radical prostatectomy did not appear to have a benefit compared to watchful waiting. He said those results, however, could be because the study involved older participants who had other chronic health problems.

Rider said the study results aren't definitive, but she thinks the findings add important information to the debate.

 

Reliable pretreatment information assists prostate cancer patients in decision-making

Men who have been diagnosed with prostate cancer need to assimilate information rapidly in order to weigh the treatment options and make informed decisions. Although patients consult a variety of information sources, outcome information that is specific to the treating physician leads to greater patient satisfaction following treatment, according to a new study published in The Journal of Urology®.

The benefits of patient information are broad. For many people confronted with a cancer diagnosis, information translates to greater involvement in management decisions, improved ability to cope, reduced anxiety and distress, better communication with family members, and increased satisfaction with treatment choices.

"The availability and quality of information are particularly relevant in prostate cancer, which affects a large number of men and is associated with significant treatment-related side effects. Despite its high prevalence, though, we know relatively little about the use and helpfulness of patient information materials among prostate cancer patients," says lead investigator John T. Wei, MD, MS, of the Department of Urology, University of Michigan Health System, Ann Arbor.

Researchers conducted a prospective, multicenter study on the use of information and satisfaction among a sample of men recently diagnosed with early stage prostate cancer undergoing definitive therapy. Over 1,200 men were enrolled in the PROST-QA (Prostate Cancer Outcomes and Satisfaction with Treatment Quality Assessment) study. Study participants completed several questionnaires before treatment and during follow-up through computer-assisted telephone interviews.

Although nearly 90% of the participants were Caucasian, 135 subjects of minority race also participated. Primary treatment included radical prostatectomy, external beam radiation therapy, or brachytherapy, with or without androgen deprivation therapy.

Researchers found that information sources used by patients varied significantly according to race, education, and study site. The most commonly used source of information was physician description (93.2%), followed by print sources such as pamphlets and brochures (82.5%). The majority of men also used other sources, including websites (68%), family and friends (63.7%), and books on prostate cancer (59.1%). Other sources, such as video media, access to other men treated for prostate cancer, and summaries of physician-specific outcomes were used less often.

The use and helpfulness of different information sources varied by factors such as age, race, education level, income, and marital status. Differences in the use of sources were apparent among men of different backgrounds. In general, younger, non-black, married men with college educations and higher incomes used more sources of information. This was most apparent in the use of Internet-based sources, where there were significant differences among men of different socioeconomic and educational backgrounds. Significant differences were also seen in the use of books, family and friends, and access to other men with previous experience with prostate cancer treatments.

"These differences may be related to knowledge of and access to greater resources, although variation in information seeking behaviors and coping mechanisms among men of different demographic backgrounds cannot be discounted," observes Wei.

"For prostate cancer patients, the impact of treatment on health-related quality of life is an important consideration. Reliable pretreatment information may allow patients to set expectations regarding treatment outcomes and make informed decisions in selecting therapy. Our results indicate that outcome information specific to the treating physician is associated with greater patient satisfaction following treatment, and that this type of information may assist patients in the decision making process," he concludes.

Pain drugs used in prostate gland removal linked to cancer outcome

The methods used to anesthetize prostate cancer patients and control pain when their prostate glands are surgically removed for adenocarcinoma may affect their long-term cancer outcomes, a study led by Mayo Clinic has found. Opioids, painkillers commonly given during and after surgery, may suppress the immune system's ability to fight cancer cells. The research suggests that supplementing general anesthesia with a spinal or epidural painkiller before a radical prostatectomy reduces a patient's need for opioids after surgery, and this finding was associated with a lower risk of cancer recurrence. The findings are published online in the British Journal of Anaesthesia.

The immune system's strength is especially important in cancer surgery because surgical manipulation of a tumor may spread cancer cells. The immune system can be impaired by general anesthesia, the overall stress surgery places on the body and by post-surgical systemic opioid use. The study found better outcomes in radical prostatectomy patients who had general anesthesia supplemented with spinal or epidural delivery of a long-acting opioid such as morphine, than in those who received general anesthesia only.

"We found a significant association between this opioid-sparing technique, reduced progression of the prostate tumor and overall mortality," says senior author Juraj Sprung, M.D., Ph.D., a Mayo Clinic anesthesiologist.

Researchers used Mayo Clinic's prostatectomy registry, anesthesia database and electronic medical records to identify patients who had prostate gland surgery for adenocarcinoma from January 1991 through December 2005. Reports of recurrence of cancer, cancer spread and death were confirmed with patients' physicians.

While promising, the findings must be tested in randomized trials, Dr. Sprung says: "Provided future studies confirm what we've found in this study, maybe down the line this would be a standard of care for pain management in patients undergoing cancer surgery."

New Procedure May Shrink Enlarged Prostate Without Surgery

Men who need treatment for an enlarged prostate may soon have a new nonsurgical option, a small, early study suggests.

Called prostatic artery embolization (PAE), the technique uses a catheter threaded into an artery in the leg. The catheter is guided to the artery that supplies blood to the prostate. Then, tiny beads are injected into the artery, which temporarily block the blood supply to the prostate.

The temporary loss of blood supply causes the prostate to shrink, relieving symptoms, according to study lead author Dr. Sandeep Bagla. What's more, the new treatment doesn't appear to have the same risk of serious complications, such as incontinence and impotence, that often accompany enlarged prostate treatment.

"This is fantastic news for the average man with benign prostatic hyperplasia. Many men decline current treatments because of the risks. But, for the average man, PAE is a no-brainer," said Bagla, an interventional radiologist at Inova Alexandria Hospital, in Virginia.

The procedure has only been available as part of Bagla's trial until recently, but he said some interventional radiologists have started doing prostatic artery embolization, and he expects the procedure will become more widely available by the end of the year.

Benign prostatic hyperplasia is the medical term for an enlarged prostate. An enlarged prostate is very common as men get older. As many as half of all men in their 60s will have an enlarged prostate, according to the U.S. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). By the time men are in their 70s and 80s, up to 90 percent have benign prostatic hyperplasia, according to the NIDDK.

Some men experience no symptoms, while others may feel the need to urinate frequently, but they have a weak urinary stream, the NIDDK says. There are a number of treatments available for benign prostatic hyperplasia, including medications and surgery.

Bagla said that interventional radiologists in Europe and South America have been using prostatic artery embolization, and that the current study is the first in the United States to test the procedure.

He and his colleagues hope to treat a total of 30 patients, but they're reporting on the results from the first 18 patients on Monday at the annual meeting of Society of Interventional Radiology, in New Orleans. The data and conclusions should be viewed as preliminary until published in a peer-reviewed journal.

For the study, the average age of the patients who underwent prostatic artery embolization was 67 years. None of the men had to be admitted to the hospital after the procedure.

Ninety-four percent of the men (17 of 18) had a significant decrease in their symptoms one month after surgery. And, none reported any major complications following the surgery.

Bagla said the exact cost of the new procedure is difficult to estimate right now, but prostatic artery embolization will be cheaper than most of the currently used procedures, he said, because there's no need for an operating room and overnight hospital stays. In addition, he said, because the new procedure doesn't appear to cause complications, that will save health care dollars as well.

"This may become part of the armamentarium of treatments that can be offered for [benign prostatic hyperplasia]," said Dr. Art Rastinehad, director of interventional urologic oncology at North Shore-LIJ Health System in New Hyde Park, N.Y. He was not involved with the new study.

"This was a small series and a limited study to draw significant conclusions from. But, it's very exciting to see it evaluated and moving forward," he said.

New Study Questions Prostate Cancer Screening for Older Men

Only one-third of men over age 65 who receive an abnormal result from their PSA test actually undergo prostate biopsy to look for disease, a new study finds.

Prostate-specific antigen (PSA) screening is a common test that measures the level of a key marker for prostate cancer in the blood. In general, the higher the level of this protein, the more likely it is that a man has prostate cancer, according to the U.S. National Cancer Institute.

The value of the PSA test has recently come into question, however, with several studies suggesting it causes men more harm than good -- spotting too many slow-growing tumors that, especially in older patients, may never lead to serious illness or death.

The new study focused on this issue once again, tracking outcomes for nearly 300,000 men, aged 65 and older, who underwent PSA screening in the U.S. Veterans Affairs health care system in 2003. The men's health was followed for up to five years.

There were more than 25,000 men with clinically abnormal PSA levels. According to the study authors, during the five-year follow-up period, only 33 percent of those men underwent at least one prostate biopsy to check for evidence of cancer. About 63 percent of those who did have a biopsy were diagnosed with prostate cancer, of whom 82 percent were treated for their cancer.

The older the man, the less likely he was to have a prostate biopsy after having an abnormal PSA screening test result. Men with other health problems were also less likely to undergo a prostate biopsy, the investigators reported.

The study was published online April 15 in the journal JAMA Internal Medicine.

Among men with biopsy-detected prostate cancer, the risk of death from causes other than prostate cancer increased with age and with the presence of other health problems, Dr. Louise Walter, of San Francisco Veterans Affairs Medical Center, and colleagues pointed out in a journal news release.

Two experts not connected to the study said the findings weren't surprising, given the patients' ages.

"PSA screening has been controversial as it has a relatively low yield for finding clinically significant cancer as well as potential complications and expense related to diagnosis and treatment," said Dr. Louis Kavoussi, chairman of urology at North Shore-LIJ's Arthur Institute for Urology in New Hyde Park, N.Y.

In the new study, "as age and other chronic illnesses of aging increased, the less likely biopsy was performed," he said. "This makes sense as the authors report that older individuals and those with [other illnesses] are more likely to die of a non-prostate cancer-related cause."

Therefore, the decision to test for PSA levels in older men must take into account their relatively low risk of dying of prostate cancer, Kavoussi said. "Overall, it is known that about 10 percent of individuals diagnosed with prostate cancer succumb to the disease," he said. "In this older patient population study it was 2.2 percent -- much lower, but not zero."

Another expert agreed, saying that younger men may benefit most from regular PSA screening.

"For screening to be effective, we need to focus on men with a long life expectancy," said Dr. Stacy Loeb, assistant professor in the department of population health at NYU Langone Medical Center, New York City. "Screening allows us to diagnose the life-threatening cancers in time for cure [but] diagnosis does not mandate treatment," she explained.

"Once a diagnosis is made, many patients with low risk disease can be safely monitored conservatively," Loeb said. "Men should be actively involved in all of these choices, with a discussion about risks and benefits."

What's really needed, according to Kavoussi, is a screen that can tell a patient whether his prostate cancer is aggressive or not.

There's a "need for better ways of detecting clinically significant disease in this older population, both to avoid overtreatment and to minimize the risk of missing significant disease," Kavoussi said.

More information

The U.S. National Cancer Institute has more about prostate cancer screening.

On-and-off approach to prostate cancer treatment may compromise survival

Taking a break from hormone-blocking prostate cancer treatments once the cancer seems to be stabilized is not equivalent to continuing therapy, a new large-scale international study finds.

Based on previous smaller studies, it looked like an approach called intermittent androgen deprivation therapy might be just as good as continuous androgen deprivation in terms of survival while meanwhile giving patients a breather from the side effects of therapy. In fact, researchers believed intermittent therapy might help overcome treatment resistance that occurs in most patients with metastatic hormone-sensitive prostate cancer.

But this new study, which treated 1,535 patients with metastatic prostate cancer and followed them for a median of 10 years, finds that's not the case. Results appear in the New England Journal of Medicine.

"We tried to see whether intermittent androgen deprivation is as good as continuous androgen deprivation, but we did not prove that. We found that intermittent therapy is certainly not better and moreover we cannot even call it comparable," says lead study author Maha Hussain, M.D., FACP, a prostate cancer expert oncologist at the University of Michigan Comprehensive Cancer Center.

The study was sponsored by SWOG, a National Cancer Institute-supported cancer clinical trials cooperative group.

In the study, men with metastatic hormone-sensitive prostate cancer were given an initial course of androgen deprivation therapy (hormone therapy), which is standard therapy for this disease. Patients with a stable or declining PSA level equal to or below a cut-off of 4 ng/ml were then randomly assigned either to continue or to discontinue the hormone therapy. Patients were carefully monitored with monthly PSAs and a doctor's evaluation every three months and therapy was resumed in the intermittent arm when PSA climbed to 20 ng/ml. The intermittent cycle continued on-and-off based on the PSA levels.

Survival among the two groups showed a 10 percent relative increase in the risk of death with intermittent therapy, with average survival of 5.8 years for the continuous group and 5.1 years for the intermittent group from the time of randomization.

Further, the researchers looked at quality of life between the two groups of patients. Initially the intermittent therapy group showed significant improvement in impotence and emotional function in the first three months and had improved trends in other aspects of quality of life compared to the continuous group. But these differences leveled off over time.

"The improvements in some aspects of quality of life that were observed early were not sustained after a few months as patients had to resume therapy," says Hussain professor of internal medicine and urology at the U-M Medical School.

"If a patient is coming in with newly metastatic prostate cancer, hormone treatment continuously is the standard. If they wish to do intermittent treatment, they should be counseled that based on this data, their outcome might be compromised," she adds.

Leading Experts Disagree On Evidence Behind Prostate Cancer Screening Recommendations

Do the results of recent randomized trials justify the recent U.S. recommendation against yearly measurement of prostate-specific antigen (PSA) as a screening test for prostate cancer? That's the topic of debate in a special "point/counterpoint" section in the April issue of Medical Care.

The recommendation against routine PSA measurement relies too heavily on randomized trial data, according to an article by Ruth Etzioni, PhD, of Fred Hutchinson Cancer Research Center, Seattle, and colleagues. They argue that modeling studies provide a truer picture of the long-term benefits of PSA screening. But Dr Joy Melnikow of University of California, Davis, and colleagues disagree, asserting that randomized trials provide a sufficient level of certainty to recommend against PSA screening.

Point: Short-Term Trials Don't Reflect Long-Term Risk Last year, the U.S. Preventive Services Task Force recommended against routine PSA measurement to screen for prostate cancer. The recommendation was mainly based on two recent studies -- one conducted in Europe and one in the United States -- in which men were randomly assigned to annual PSA screening or no screening. Both studies concluded that annual screening did not reduce the risk of death from prostate cancer.

But randomized trials have important limitations as a basis for screening policies, according to Dr Etzioni and colleagues. They note that screening trials generally provide short-term results, in contrast to the long-term results generated by population-wide screening programs. They argue that taking the randomized trial data at face value "misrepresents the likely long-term population impact of PSA screening (relative to no screening) in the United States."

Dr Etzioni and coauthors discuss the results of modeling studies that give a different picture of the benefits of PSA screening. Based on those models, screening may explain 45 percent of recent declines in U.S. deaths from prostate cancer, while changes in treatment account for 33 percent. When the randomized trial data are extrapolated to the U.S. population over the long term, the absolute reduction in deaths attributed to screening appears at least five times greater than in the original trial reports.

Modeling studies also suggest a lower rate of overdiagnosis -- screening detection of slow-growing prostate cancers that otherwise would have caused no harm -- than reported in the trials. Dr Etzioni and colleagues conclude, "With a disease whose hallmark is a lengthy natural history, the harms of developing cancer screening policies based primarily on limited-duration screening trials may well outweigh the benefits."

Counterpoint: Trials Are Best Evidence on Screening Effects But in their "Counterpoint" essay, by Dr Melnikow and colleagues notes that the U.S. and European trials provided 11 to 13 years' follow-up in more than 250,000 individuals. They also point out that the U.S. trial was highly representative of the population and showed no reduction in death resulting from annual PSA testing. (Dr Melnikow and colleagues were members of the U.S. Preventive Services Task Force when the recommendation was made.)

They add that, because of "competing causes of death," it becomes even less likely that a large reduction in deaths from prostate cancer will appear over long-term follow-up. The chances of overdiagnosis and potential harms from screening are also likely to increase with continued aging. Dr Melnikow and coauthors conclude, "Projections from models are subject to mistaken assumptions and investigator biases, and should not be accorded the same weight as evidence from randomized controlled trials."

In an editorial response, Dr Etzioni's group points out that modeling plays an essential role in addressing questions about the harms and benefits of screening. "While we acknowledge the centrality of screening trials in the policy process," they write, "we maintain that modeling constitutes a powerful tool for screening trial interpretation and screening policy development."

The debate is "no mere academic exercise," according to an editorial by Ronnie D. Horner, PhD, of University of Cincinnati Medical Center. With the increased emphasis on disease prevention under health care reform, it is essential to offer those services most likely to represent value -- including cancer screenings. While there's no easy answer, Dr Horner writes, "I am hopeful that this Point-Counterpoint exchange will initiate a discussion among healthcare scientists that will yield greater guidance for determining whether a health care service is, indeed, value health care."

Surgery Is Superior to Radiotherapy in Men With Localized Prostate Cancer

Surgery offers better survival benefit for men with localised prostate cancer, according to a large observational study, conducted by a group of researchers in Sweden and the Netherlands.

"The current gold standard management of localised prostate cancer is radical therapy, either as surgery or radiation therapy. This study suggests that surgery is likely superior to radiation for the majority of men who have localized prostate cancer, especially the younger age group and those with no or few comorbidities," said Dr. Prasanna Sooriakumaran, lead study author, of the Karolinska University Hospital in Stockholm.

In their study, Sooriakumaran and colleagues compared the oncologic effectiveness of radical prostatectomy and radiotherapy in prostate cancer, and analysed the mortality outcomes in 34,515 patients treated with up to 15 years follow-up.

Data from Sweden's National Prostate Cancer Registry showed that the men were treated for prostate cancer throughout Sweden with either surgery (n=21,533) or radiotherapy (n=12,982) as their first treatment option and form the study cohort. Patients were categorised by risk group (localised- low risk, localised- intermediate risk, localised- high risk, and non-localized- any T3-4, N+, M+, PSA>50), age (<65, 65-74, ≥75), and Charlson co-morbidity index or CCI (0, 1, ≥2).

In their results, the researchers said radiotherapy patients generally had higher Gleason sums and clinical stages, were older, and had higher PSA than patients that underwent surgery (p<0.0001 for all comparisons). Prostate-cancer-mortality (PCM) became a larger proportion of overall mortality as risk group increased for both the surgery and radiotherapy cohorts. The study also showed that for localised prostate cancer patients (risk groups 1-3) survival outcomes favored surgery, and for locally advanced/metastatic patients treatment results were similar.

"This study may herald an increasing use of surgery over radiation in this group. Also, our study concluded that for men with advanced prostate cancer, both modalities appear equivalent and thus the conventional view that surgery is not indicated in this group may be incorrect," explained Sooriakumaran. He added that with their results majority of men with low risk prostate cancer do not die of the disease.

"A very long follow up period is needed to make any comments regarding comparative oncologic outcomes between treatments. Hence, the use of active surveillance may be appropriate in men with low risk disease," Sooriakumaran pointed out.

However, men with intermediate and high-risk disease are at relatively high probability to die from prostate cancer. "Especially when we look at the absolute numbers involved," he said, adding that radical treatment, preferably in the form of surgery, is warranted if possible.

The study won the second prize for best abstract in oncology at the 28th Annual EAU Congress which will opened in Milan on March 15.

MUSHROOM-SUPPLEMENTED SOYBEAN EXTRACT SHOWS THERAPEUTIC PROMISE FOR ADVANCED PROSTATE CANCER

A natural, nontoxic product called genistein-combined polysaccharide, or GCP, which is commercially available in health stores, could help lengthen the life expectancy of certain prostate cancer patients, UC Davis researchers have found.

Men with prostate cancer that has spread to other parts of the body, known as metastatic cancer, and who have had their testosterone lowered with drug therapy are most likely to benefit. The study, recently published in Endocrine-Related Cancer, was conducted in prostate cancer cells and in mice.

Lowering of testosterone, also known as androgen-deprivation therapy, has long been the standard of care for patients with metastatic prostate cancer, but life expectancies vary widely for those who undergo this treatment. Testosterone is an androgen, the generic term for any compound that stimulates or controls development and maintenance of male characteristics by binding to androgen receptors.

The current findings hold promise for GCP therapy as a way to extend life expectancy of patients with low response to androgen-deprivation therapy.

Paramita Ghosh, an associate professor in the UC Davis School of Medicine, led the pre-clinical study with a team that included UC Davis Comprehensive Cancer Center Director Ralph de Vere White, a UC Davis distinguished professor of urology. Ruth Vinall in the UC Davis Department of Urology and Clifford Tepper in the UC Davis Department of Biochemistry and Molecular Medicine directed the studies in mice; Ghosh’s laboratory conducted the cell studies.

The research focused on GCP, a proprietary extract cultured from soybeans and shiitake mushrooms and marketed by Amino-Up of Sapporo, Japan. Researchers found that the combination of the compounds genistein and daidzein, both present in GCP, helps block a key mechanism used by prostate cancer cells to survive in the face of testosterone deprivation.

The research team had earlier shown that when a patient’s androgen level goes down, cancerous prostate cells kick out a protein known as filamin A, which is otherwise attached to the androgen receptor in the cell’s nucleus. The androgen receptor regulates growth of prostate cancer cells. Once filamin A leaves the cancerous cell’s nucleus, that cell no longer requires androgens to survive. Thus, loss of filamin A allows these cells to survive androgen deprivation, at and the cancer essentially becomes incurable.

The paper, titled “Enhancing the effectiveness of androgen deprivation in prostate cancer by inducing Filamin A nuclear localization,” shows for the first time that GCP keeps filamin A in the nucleus. As long as this protein remains attached to the androgen receptor, the cancerous cells need androgens to survive and grow. They die off when starved of androgens, thus prolonging the effects of androgen deprivation, which ultimately prolongs the patient’s life.

The team’s hypothesis is that metastatic prostate cancer patients with the weakest response to androgen-deprivation therapy could be given GCP concurrently with androgen deprivation therapy to retain Filamin A in the nucleus, thereby allowing cancer cells to die off.

De Vere White is now pursuing funding to begin GCP human clinical trials. Because GCP is a natural product rather than a drug, and requires fewer government approvals, it’s expected that these trials will proceed rapidly once funded.

“We should know within the first eight months or so of human clinical trials if GCP works to reduce PSA levels,” says de Vere White, referring to prostate-specific antigen levels, a tumor marker to detect cancer. “We want to see up to 75 percent of metastatic prostate cancer patients lower their PSA levels, and GCP holds promise of accomplishing this goal. If that happens, it would probably be a greater therapy than any drug today.”

New Compound Holds High Promise in Battling Kidney Cancer

Chemists at the University of California, Riverside have developed a compound that holds much promise in the laboratory in fighting renal (kidney) cancer.

Named TIR-199, the compound targets the "proteasome," a cellular complex in kidney cancer cells, similar to the way the drug bortezomib, approved by the Food and Drug Administration, targets and inhibits the proteasome in multiple myeloma cells, a cancer coming from bone marrow.

Michael Pirrung, a distinguished professor of chemistry at UC Riverside, announced the development of TIR-199 in a lecture he gave on Feb. 19 at the 5th International Conference on Drug Discovery and Therapy, held in Dubai, UAE.

Operating like the garbage dump of a cell, the proteasome breaks down proteins. Drugs that block the action of proteasomes are called proteasome inhibitors, and have been shown to have activity against a variety of cancer cell lines, albeit with mixed results. For example, bortezomib, though effective against multiple myeloma, has many side effects because cells other than bone marrow cells are affected.

"The novel feature of our new proteasome inhibitor, TIR-199, is that it is nearly as potent as bortezomib, but is selective in inhibiting the growth of only renal cancer cell lines," Pirrung said. "It's what makes TIR-199 attractive."

The TIR-199 research project at UC Riverside began about four years ago after a multidisciplinary, international team reported on a class of compounds that act on the proteasome. These compounds are the "syringolin" natural products -- such as a compound produced naturally by the wheat-infecting bacterium Pseudomonas syringae. TIR-199 is a synthetic relative of syringolin.

"At UCR we began to work on, and completed the synthesis of, two compounds from this class of compounds," Pirrung said. "Of the two, TIR-199 showed most promise."

Pirrung's lab first shipped TIR-199 samples to the University of Hawaii, Hilo, where André Bachmann, an associate professor of pharmaceutical sciences and Pirrung's collaborator, studied TIR-199 in test-tube assays for how it worked against the proteasome. Bachmann then tested the compound against a limited number of cancer cell lines that showed that TIR-199 was effective against the cancer cells. What remained unclear, however, was if TIR-199 was toxic to normal cells.

Encouraged by these results, Pirrung submitted TIR-199 samples to the National Cancer Institute at the National Institutes of Health, where the compound was subjected to a rigorous 60-cell screening used routinely to test compounds for their effectiveness in battling 60 kinds of cancer, including leukemia, lung, colon, brain, breast, ovarian prostate and renal cancers.

"We were very excited when the NCI informed us that TIR-199 has excellent potential to be moved to drug development because of its selective activity against renal cancer," Pirrung said. "This is good news also because the NCI scientists told us there really are no good drugs out there to fight renal cancer."

Next, the NCI will test TIR-199 on cells grown in a hollow fiber that partially mimics the body by offering a three-dimensional environment. If the test results are positive, TIR-199 will be tested on mice.

The UCR Office of Technology Commercialization has filed a patent application on TIR-199 and is currently seeking partners in industry interested in developing the compound commercially. Several biotechnology companies have already shown interest.

"We still have to fine-tune TIR-199 in the lab because some aspects -- certain structural elements within it -- make it easily metabolized," Pirrung said. "But now that we have a good handle on how structural changes in the compound affect anticancer activity and how the parent drug binds to the proteasome, we are pretty confident of making a better version -- the second generation -- of TIR-199."

The project was funded by a grant from the University of California Institute for Mexico and the United States (UC MEXUS), to Tannya Ibarra-Rivera, a former postdoctoral researcher in Pirrung's lab who helped discover TIR-199 and after whose initials the compound is named; and to Pirrung from the UC Cancer Research Coordinating Committee.

Men at ‘High’ Skeletal Risk Prior to Prostate Cancer Hormone Therapy Likely to Have More Fractures After Treatment

In what is believed to be the first study to describe the impact on men with a ‘high’ risk of bone fracture who are receiving long-term androgen deprivation therapy (ADT) for prostate cancer, new research from The Cancer Institute of New Jersey shows this population to have a higher fracture incidence following treatment completion. The findings, published in the latest online version of BJU International (doi:10.1111/j.1464-410X.2012.11758.x), also show that men who experienced a fracture had a 1.38-fold higher mortality risk than those who did not. The Cancer Institute of New Jersey is a Center of Excellence of the University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School (RWJMS).

Men with localized prostate cancer who have underlying health conditions often receive this type of therapy with the hope to shrink or delay growth of their cancer, because they are considered inappropriate candidates for more aggressive therapies such as surgery or radiation. Previous studies have shown an association between the receipt of ADT for prostate cancer and an increased risk of bone fracture and other skeletal complications, such as a decrease in bone mineral density. The investigators at The Cancer Institute of New Jersey further explored the impact of this treatment on men already deemed to be at high risk for fracture prior to receiving therapy.

Using the population-based Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database, researchers reviewed information on demographics and tumor characteristics from 75,994 men aged 66 and older who were diagnosed as having localized prostate cancer from 1992 to 2007. All of the SEER registries hold the highest level of certification of data quality. A risk assessment scale for baseline skeletal complications - including fracture - was created, utilizing the presence of certain conditions within one year prior to cancer diagnosis. These conditions included diabetes, alcohol and cigarette use, paralysis, and liver disease.

Investigators found that during a 12-year follow up, more than 58 percent of men deemed at high fracture risk prior to treatment and 38 percent considered at low risk developed at least one fracture following ADT. The research also showed that men with a high baseline risk had a higher probability of receiving ADT (52.1 percent) compared to those with a low baseline risk (38.2 percent). It was also determined that those men receiving ADT by itself were likely to have a stronger dose than those who received ADT in combination with other treatments for their prostate cancer. Mortality risk was found to be 40 percent higher within two years after experiencing a fracture.

“Our findings suggest that treating men having a high baseline risk of fracture with long-term androgen deprivation therapy may have serious adverse consequences,” said senior author Grace Lu-Yao, PhD, MPH, cancer epidemiologist at The Cancer Institute of New Jersey and professor of medicine at Robert Wood Johnson Medical School and of epidemiology at UMDNJ-School of Public Health. “We anticipate the results of this study will prompt further examination of a patient’s baseline-risk of fracture and skeletal complications prior to administering this course of therapy.”

The authors note the use of bisphosphonates, which are effective in preventing bone loss in patients with prostate cancer receiving ADT, was not available in the SEER-Medicare linked data. Information regarding a patient’s height and weight, which can be considered risk factors for skeletal complications, also was not available. Data on men younger than 66 were not examined. Despite these limitations, Dr. Lu-Yao, says their investigation shines new light on a large subset of men who commonly receive ADT.

Change in PSA levels over time can help predict aggressive prostate cancer

Measurements taken over time of prostate specific antigen, the most commonly used screening test for prostate cancer in men, improve the accuracy of aggressive prostate cancer detection when compared to a single measurement of PSA, according to a Kaiser Permanente study published today in the British Journal of Urology International.

The retrospective study examined the electronic health records of nearly 220,000 men ages 45 and older over a 10-year period who had at least one PSA measurement and no previous diagnosis of prostate cancer. The study found that annual percent changes in PSA more accurately predicted the presence of aggressive prostate cancer when compared to single measurements of PSA alone, but only marginally improved the prediction of prostate cancer overall.

"The use of a single, elevated PSA level to screen for prostate cancer is considered controversial given the questionable benefits of PSA screening on prostate cancer mortality. The screening may also result in unnecessary prostate biopsies and subsequent treatments for localized prostate cancer, as it does not distinguish well between slow-growing and aggressive disease," said Lauren P. Wallner, PhD, MPH, study lead author and post-doctoral research fellow at Kaiser Permanente Southern California's Department of Research & Evaluation. "Our study demonstrates that repeated measurements of PSA over time could provide a more accurate – and much needed – detection strategy for aggressive forms of prostate cancer."

Men in the study were also found to experience a 2.9 percent change in PSA levels per year on average and that the rate of change in PSA increased modestly with age.

"The results of this study could provide clinicians with a better prostate cancer preventive strategy that could help differentiate between men with an aggressive form of the disease and those who have slow-growing, indolent cancer that may not necessarily merit treatment," said Wallner. "While we do not suggest that patients proactively seek out additional PSA measurements, men who already have had multiple PSAs may consider discussing the change in their PSA levels with their clinician when determining future treatment strategies."

The PSA test measures the level of prostate specific antigen, a substance made by the prostate, in a man's blood. It is one of the most commonly used tests to screen for prostate cancer, according to the Centers for Disease Control and Prevention. As a rule, the higher the PSA level in the blood, the more likely a prostate problem is present. But many factors, such as age, race, and non-cancerous conditions can affect PSA levels. The CDC and other federal agencies follow the prostate cancer screening recommendations set forth by the U.S. Preventive Services Task Force, which recommends against PSA-based screening for men who do not have symptoms. Kaiser Permanente guidelines include a recommendation that men age 40 and older should discuss the PSA test and rectal exam with their physician.

Aside from non-melanoma skin cancer, prostate cancer is the most common cancer among men in the United States, according to the CDC. In 2008 (the most recent year numbers are available), nearly 215,000 men in the United States were diagnosed with prostate cancer and more than 28,000 men died from the disease. Prostate cancer is the second most common cause of death from cancer among white, African American, American Indian/Alaska Native and Hispanic men, and is more common in African-American men than white men, according to the CDC.

How prostate cancer therapies compare by cost and effectiveness

Surgery ranks as the most cost-effective type of treatment, according to UCSF-led study


The most comprehensive retrospective study ever conducted comparing how the major types of prostate cancer treatments stack up to each other in terms of saving lives and cost effectiveness is reported this week by a team of researchers at the University of California, San Francisco (UCSF).

Appearing in the British Journal of Urology International, the work analyzed 232 papers published in the last decade that report results from clinical studies following patients with low-, intermediate- and high-risk forms of prostate cancer who were treated with one or more of the standard treatments – radiation therapy, surgery, hormone therapies and brachytherapy.

The analysis shows that for people with low-risk prostate cancer, the various forms of treatment vary only slightly in terms of survival – the odds of which are quite good for men with this type of cancer, with a 5-year cancer-specific survival rate of nearly 100 percent. But the cost of radiation therapy is significantly more expensive than surgery for low-risk prostate cancer, they found.

For intermediate- and high-risk cancers, both survival and cost generally favored surgery over other forms of treatment – although combination external-beam radiation and brachytherapy together were comparable in terms of quality of life-adjusted survival for high-risk prostate cancer.

"Our findings support a greater role for surgery for high-risk disease than we have generally seen it used in most practice settings," said urologist Matthew Cooperberg, MD, MPH who led the research. Cooperberg is an assistant professor of urology and epidemiology and biostatistics in the UCSF Helen Diller Family Comprehensive Cancer Center.

The UCSF Helen Diller Family Comprehensive Cancer Center is one of the country's leading research and clinical care centers, and it is the only comprehensive cancer center in the San Francisco Bay Area.

Many Treatment Options, but Few Cost Analyses

Localized prostate cancer accounts for about 81 percent of the quarter-million cases of prostate cancers that occur in the United States every year, according to the National Cancer Institute. It is defined by tumors that have not metastasized and spread outside the prostate gland to other parts of the body.

There are multiple types of treatment for this form of the disease, including various types of surgery (open, laparoscopic or robot-assisted); radiation therapy (dose-escalated three-dimensional conformal radiation therapy, intensity-modulated radiation therapy and brachytherapy); hormone therapies; and combinations of each of these. Many men with low-risk prostate cancer do not need any of these treatments, and can be safely observed, at least initially.

Treatment plans for localized prostate cancer often vary dramatically from one treatment center to another. As Cooperberg put it, one person may have surgery, while someone across town with a very similar tumor may have radiation therapy, and a third may undergo active surveillance. All treatment regimens may do equally well.

"There is very little solid evidence that one [approach] is better than another," said Cooperberg. The motivation for the new study, however, was that there are also few data examining the differences in terms of cost-effectiveness – the price to the health care system for every year of life gained, with adjustment for complications and side effects of treatments.

The new study was the most comprehensive cost analysis ever, and it compared the costs and outcomes associated with the various types of treatment for all forms of the disease, which ranged from $19,901 for robot-assisted prostatectomy to treat low-risk disease, to $50,276 for combined radiation therapy for high-risk disease.

The study did not consider two other approaches for dealing with prostate cancer: active surveillance, where patients with low-risk cancer are followed closely with blood tests and biopsies and avoid any initial treatment; and proton therapy, which is much more expensive and has already been shown in multiple studies not to be cost-effective, said Cooperberg.

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The article, "Primary treatments for clinically localised prostate cancer: a comprehensive lifetime cost-utility analysis" is authored by Matthew R. Cooperberg, Naren R. Ramakrishna, Steven B. Duff, Kathleen E. Hughes, Sara Sadownik, Joseph A. Smith and Ashutosh K. Tewari. It was published online on Dec. 28, 2012 by the British Journal of Urology International. The article can be accessed at: http://dx.doi.org/10.1111/j.1464-410X.2012.11597.x

Resveratrol Could Be Key to Fighting Prostate Cancer

Resveratrol, a compound found commonly in grape skins and red wine, has been shown to have several beneficial effects on human health, including cardiovascular health and stroke prevention. Now, a University of Missouri researcher has discovered that the compound can make prostate tumor cells more susceptible to radiation treatment, increasing the chances of a full recovery from all types of prostate cancer, including aggressive tumors.

"Other studies have noted that resveratrol made tumor cells more susceptible to chemotherapy, and we wanted to see if it had the same effect for radiation therapy," said Michael Nicholl, an assistant professor of surgical oncology in the MU School of Medicine. "We found that when exposed to the compound, the tumor cells were more susceptible to radiation treatment, but that the effect was greater than just treating with both compounds separately."

Prostate tumor cells contain very low levels of two proteins, perforin and granzyme B, which can function together to kill cells. However, both proteins need to be highly "expressed" to kill tumor cells. In his study, when Nicholl introduced resveratrol into the prostate tumor cells, the activity of the two proteins increased greatly. Following radiation treatment, Nicholl found that up to 97 percent of the tumor cells died, which is a much higher percentage than treatment with radiation alone.

"It is critical that both proteins, perforin and granzyme B, are present in order to kill the tumor cells, and we found that the resveratrol helped to increase their activity in prostate tumor cells," Nicholl said. "Following the resveratrol-radiation treatment, we realized that we were able to kill many more tumor cells when compared with treating the tumor with radiation alone. It's important to note that this killed all types of prostate tumor cells, including aggressive tumor cells."

Resveratrol is present in grape skins and red wine and available over-the-counter in many health food sections at grocery stores. However, the dosage needed to have an effect on tumor cells is so great that many people would experience uncomfortable side effects.

"We don't need a large dose at the site of the tumor, but the body processes this compound so efficiently that a person needs to ingest a lot of resveratrol to make sure enough of it ends up at the tumor site. Because of that challenge, we have to look at different delivery methods for this compound to be effective," Nicholl said. "It's very attractive as a therapeutic agent since it is a natural compound and something that most of us have consumed in our lifetimes."

Nicholl said that the next step would be to test the procedure in an animal model before any clinical trials can be initiated. Nicholl's studies were published in the Journal of Andrology and Cancer Science. The early-stage results of this research are promising. If additional studies, including animal studies, are successful within the next few years, MU officials will request authority from the federal government to begin human drug development (this is commonly referred to as the "investigative new drug" status). After this status has been granted, researchers may conduct human clinical trials with the hope of developing new treatments for cancer.

Depression increased bladder cancer mortality

As part of an ongoing, large-scale epidemiologic study of bladder cancer, Chen and colleagues collected clinical and mental health information on 464 patients with bladder cancer. They assessed patients' depression levels with the Center for Epidemiologic Studies Depression Scale (CES-D).

Depression symptoms alone affected mortality: Patients with CES-D scores of 16 or greater had a median survival time of 58 months, while those with scores below 16 had a median survival time longer than 200 months. In addition, patients with CES-D scores of 16 or greater had a 1.89-fold increased risk for all-cause mortality compared with patients with CES-D scores less than 16.

In addition, the researchers pointed to evidence that smoking cessation, weight loss and increased physical activity can potentially improve survival.

"In terms of building a prediction model for bladder cancer mortality, current models only focus on clinical variables, such as treatment and tumor stage and grade," Chen said. "Our study suggests that psychological factors and perhaps lifestyle changes could be included in this prediction model."

Like prostate cancer, bladder cancer patients may benefit from anti-androgen therapy

Bladder cancer patients whose tumors express high levels of the protein CD24 have worse prognoses than patients with lower CD24. A University of Colorado Cancer Center study published today in the Proceedings of the National Academy of Sciences shows that CD24 expression may depend on androgens – and that anti-androgen therapies like those currently used to treat prostate cancer may benefit bladder cancer patients.

MRI helps identify patients with prostate cancer who may benefit from active surveillance

In the quest to prevent prostate cancer overtreatment, "active surveillance" has emerged as a plausible option, encouraged for men whose tumors may not need immediate treatment and may never progress to more serious illness. A group of investigators from Memorial Sloan-Kettering Cancer Center report that adding endorectal magnetic resonance imaging to the initial clinical evaluation of men with clinically low prostate cancer risk helps assess eligibility for active surveillance. Their results are published in The Journal of Urology.

Golden Age of Prostate Cancer Treatment Hailed as Fourth Drug in Two Years Extends Life

The head of one of the UK's leading cancer research organisations has hailed a golden age in prostate cancer drug discovery as for the fourth time in two years results are published finding a new drug can significantly extend life.

A study in the New England Journal of Medicine August 15 shows the drug enzalutamide can significantly extend life and improve quality of life in men with advanced prostate cancer -- in findings that could further widen the treatment options for men with the disease.

The Institute of Cancer Research, London, and its partner hospital The Royal Marsden NHS Foundation Trust jointly led the new Phase III trial of enzalutamide and the Phase III trials of two other drugs, cabazitaxel and abiraterone. Abiraterone was also discovered at The Institute of Cancer Research and was recently made available on the NHS. A further drug sipuleucel-T has also been shown to extend life in the two-year period.

Professor Alan Ashworth, chief executive of The Institute of Cancer Research (ICR), said cancer research in the UK was finally delivering new treatment options for men with advanced prostate cancer after a long period where the options were limited.

Professor Ashworth said: "Advanced prostate cancer is extremely difficult to treat, and it's taken a massive coordinated effort to finally bring new drugs into the pipeline, after decades where there were no options once old-style hormone treatment stopped working.

"What we're seeing now is an unprecedented period of success for prostate cancer research, with four new drugs shown to extend life in major clinical trials in just two years, and several others showing promise. It truly is a golden age for prostate cancer drug discovery and development."

Professor Martin Gore, medical director of The Royal Marsden Hospital, said: "We are delighted with the recent progress that has been made in the treatment of advanced prostate cancer and to see the impact this is having on our patients, many of whom are living longer with a better quality of life as the result of these new drugs."

Enzalutamide, a new type of hormone treatment, was assessed in 1,199 patients with metastatic castration-resistant prostate cancer that had previously received chemotherapy, in a multinational, randomised placebo-controlled trial sponsored by pharmaceutical companies Medivation and Astellas.

Median survival with enzalutamide was 18.4 months, compared with 13.6 months for men receiving a placebo. Around 43 per cent of men taking enzalutamide as part of the AFFIRM trial reported an improved quality of life, compared with 18 per cent of men taking a placebo. In November last year, the trial's Independent Data Monitoring Committee recommended that the trial be stopped early and men who received the placebo be offered enzalutamide.