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.”