Intermittent Hormone Therapy for Prostate Cancer Inferior to Continuous Therapy

Many men with metastatic, hormone-sensitive prostate cancer live longer on continuous androgen-deprivation therapy (also known as hormone therapy) than on intermittent therapy, according to a seventeen-year study led by SWOG, a cancer research cooperative group funded by the National Cancer Institute (NCI).

Men with newly diagnosed metastatic prostate cancer are usually either surgically castrated or given medications to suppress the production of male hormones that drive their cancer. The treatment can help keep the disease at bay temporarily, but in the majority of patients the cancer will relapse and contribute to the patient’s death.

Surgical castration is permanent but “medical castration” provides men the potential advantage of receiving therapy intermittently. A halt in this therapy is followed in time by a rise in testosterone levels. Scientific data suggested that intermittent treatment may delay the cancer relapse, and that the rise in testosterone may result in an improvement in the patient’s quality of life.

These data provided the rationale for the phase III clinical trial SWOG-9346, the largest such study to date in men with metastatic, hormone-sensitive disease. Results of this study demonstrate that intermittent androgen-deprivation (AD) therapy is not as good as continuous hormone therapy with regard to patient longevity.

The findings are to be presented today at the plenary session of the American Society for Clinical Oncology’s (ASCO’s) annual meeting by the study’s principal investigator, Maha Hussain, M.D., F.A.C.P., of the University of Michigan Comprehensive Cancer Center.

“Based on these results,” Hussain says, “we can conclude that intermittent AD is not as effective as continuous AD in men with metastatic prostate cancer.”

Clinical researchers from the SWOG network, with funding from the NCI, led an international team in conducting the study at more than 500 sites, enrolling 3,040 men with hormone-sensitive, metastatic prostate cancer between 1995 and 2008.

All men got an initial course of androgen-deprivation treatment for seven months. The 1,535 eligible men whose prostate-specific antigen (PSA) level dropped to 4 ng/mL or less by the end of those seven months were then assigned at random to stop therapy (the intermittent therapy group) or continue therapy (the continuous therapy group).

Those randomized to the intermittent therapy arm had their treatment suspended until their PSA rose to a predetermined level, at which time they started another seven-month course of androgen-deprivation therapy, cycling on and off therapy in this way as long as their PSA levels continued to respond appropriately during the “on” cycle.

Men on continuous therapy had a median overall survival time of 5.8 years from the time of randomization, with 29 percent of these men surviving at least 10 years. Those on intermittent therapy had a median overall survival time of 5.1 years, with 23 percent surviving at least 10 years from the time they were randomly assigned to a treatment arm.

The researchers found, in additional analyses, that men with “minimal disease” (disease that had not spread beyond the lymph nodes or the bones of the spine or pelvis) did significantly better on continuous therapy, while men with “extensive disease” (disease that had spread beyond the spine, pelvis, and lymph nodes or to the lungs or liver) seemed to do about as well using either treatment approach.

Additional analyses indicated that the median overall survival time for those with minimal disease was 7.1 years on continuous androgen-deprivation therapy compared to only 5.2 years on intermittent treatment. Patients with extensive disease had median overall survival times of 4.4 years on continuous therapy and 5.0 years on intermittent therapy.

“In the past when it came to using hormone therapy in this disease, doctors viewed the disease as one entity and adopted a ‘one size fits all’ approach,” Hussain says. “Based on this study’s findings, it seems that one size does not necessarily fit all.”

Trial researchers also compared quality-of-life measures across the two study arms during the first 15 months following patient randomization, including measures of sexual function (impotence and libido), physical and emotional function, and energy level. They found improved sexual function in men who received intermittent therapy as compared to those on continuous therapy. A second presentation at an ASCO Poster Discussion session (morning of June 4th, Poster #25) reports on these preliminary quality-of-life findings from SWOG-9346 (Abstract #4571, CM Moinpour, DL Berry, et al).

“Though we see potential quality-of-life benefits with IAD,” Hussain says, “from a medical perspective, the primary findings of the study demonstrating that IAD is inferior with regard to overall survival should be the primary consideration in counseling all patients who are interested in intermittent therapy and particularly those with minimal disease.”

In brief: 1,535 men with metastatic, hormone-sensitive prostate cancer were randomized to intermittent androgen-deprivation (AD) therapy or continuous AD therapy after seven months of androgen deprivation._• When overall survival times were compared, intermittent AD was inferior to continuous AD._• For the subset of patients with minimal disease, continuous AD was superior to intermittent AD._• For patients with extensive disease, overall survival was comparable between intermittent and continuous AD._• A number of quality-of-life measures got higher scores in the intermittent AD arm than the continuous AD arm.

Prostate cancer statistics: More than 240,000 men in the United States will be diagnosed with prostate cancer in 2012, according to the American Cancer Society, and more than 28,000 will die of the disease.

PSA Screening Benefits Few, Harms Many, Says Panel

A US government-sponsored panel of independent experts that reviews evidence and develops recommendations for preventive clinical services says the harms of PSA-based testing for prostate cancer outweigh the benefits. The recommendation has provoked a strong and angry response from many patient and medical groups.

In a report published early online before print in the 21 May of Annals of Internal Medicine, the US Preventive Services Task Force (USPSTF) writes of PSA-based screening for prostate cancer: "[it] may benefit a small number of men but will result in harm to many others".

The USPSTF is a group of primary care physicians and epidemiologists that is appointed and funded by the US Department of Health and Human Services' Agency for Healthcare Research and Quality (AHRQ). Its recommendations are important because they influence how health policy is shaped and what insurers do. For instance, it is empowered by the Affordable Care Act to decide which screenings Americans receive.

This recommendation is the task force's "final word" on PSA-based testing. It follows a period of public comment after its last published recommendation in 2008, when at the time it concluded there was no evidence to support PSA testing for men over 75.

The task force says it has since then reviewed the evidence published since 2008 and concluded that the harms of PSA-based testing outweigh the benefits, regardless of age. The task force does not take costs into account when developing recommendations: it just weighs health benefits against harms.

The task force posted a draft of this final recommendation for public comment in October 2011. At the time it gave PSA-based screening a "D" grade, which means doctors should not offer the test to their patients because there are more harms than benefits.

Many who commented at the time suggested the "D" be changed to a "C" which says doctors could offer the test to patients who ask for it. But the panel has not changed its draft recommendation, and has stuck to the "D" grade.

According to its Annals of Internal Medicine report, the task force considered two major trials that assessed the life-saving benefits of PSA-based testing in asymptomatic men.

The first trial took place in the US. It did not show that PSA-screening reduce deaths to prostate cancer. The second trial took place in seven European countries and found PSA screening reduced deaths by one death per 1,000 men screened in a subgroup aged 5 to 69 years, mostly in two countries. The other five countries did not find a statistically significant reduction deaths.

The task force reports there is strong evidence that PSA-based screening can be harmful.

Just under 90% of men whose prostate cancer is detected via PSA undergo early treatment, either with surgery, radiation, or androgen deprivation therapy, they write. They say the evidence shows up to 5 out of every 1,000 men die within 1 month of surgery, and between 10 and 70 that survive have to live the rest of their lives with urinary incontinence, erectile and bowel dysfunction.

Statins may slow prostate growth

Statins drugs prescribed to treat high cholesterol may also work to slow prostate growth in men who have elevated PSA levels, according to an analysis led by researchers at Duke University Medical Center.

The finding, presented at the annual meeting of the American Urological Association, provides additional insight into the effects of cholesterol-lowing drugs such as statins on the prostate. Previous studies at Duke and elsewhere had found a link between statins and lower levels of PSA, a protein produced by the prostate that is often elevated by cancer or by non-lethal prostatic diseases.

In the current finding, prostatic growth rate diminished among men with elevated PSA levels who took statins, although that effect was relatively small and tapered off after about two years.

"Given that prostate enlargement is an important health problem in the United States and elsewhere, and will be a larger problem as the population ages, it's important to understand and treat its causes," said Roberto Muller, M.D., a urology fellow at Duke and lead author of the study.

Enlarged prostate, most commonly diagnosed as benign prostate hyperplasia, causes urinary problems that can escalate to bladder and kidney damage. Up to 90 percent of men over the age of 70 have some symptoms associated with enlarged prostate, according to the National Institutes of Health.

Muller and colleagues used data gathered for an unrelated, large trial originally testing whether a drug called dutasteride could help reduce the risk of prostate cancer. To test their hypothesis that statins may be associated with slower prostate growth, the researchers culled the data of more than 6,000 men, including 1,032 who also took statins.

Men on statins tended to be older than non-users, and thus were expected to have greater prostate sizes. But prostate sizes were actually similar between statin users and non-users at the start of the study. That finding provided the first suggestion that statins might affect prostate growth.

When changes in prostate growth were compared two years after the start of the trial, men in the study who took a statin drug had less prostate growth, regardless of whether they had been randomly assigned to take dutasteride or a dummy pill. Prostate growth was an average 5 percent less in men who took both a statin and dutasteride pill compared to men who took only dutasteride. For those taking a statin and a dummy pill, prostate growth was 3.9 percent less than for men taking only the placebo.

Those reductions, however, did not persist after two years.

"We don't yet understand the mechanisms that might be causing this," Muller said. "Some have suggested that statins may have anti-inflammatory properties, and inflammation has been linked to prostate growth, but this needs further study."

Muller said the findings in the current research also suggest that lifestyle choices such diet and exercise may not only affect cholesterol, but also prostate health.

"Prostate enlargement was once considered an inexorable consequence of aging and genetics, but there is growing awareness that prostate growth can be influenced by modifiable risk factors," Muller said. "In this context, the role of blood cholesterol levels and cholesterol-lowering drugs such as statins warrants further study."

Vitamin D + TB Vaccine: Allies in Fight Against Bladder Cancer?

The tuberculosis vaccine is often used as a treatment for bladder cancer, and adding vitamin D might improve the vaccine’s effectiveness, according to new research from the University of Rochester Medical Center presented today at the American Urological Association annual meeting.

Yi-Fen Lee, Ph.D., associate professor of Urology at URMC, has conducted a pre-clinical study in a mouse model showing that a combination of vitamin D therapy and the Bacillus Calmette-Guerin (BCG) vaccine greatly improves bladder cancer survival. The next phase, an early clinical trial in patients, will begin soon as part of a collaborative research project between the URMC’sJames P. Wilmot Cancer Center and the Roswell Park Cancer Institute in Buffalo.

The connection between vitamin D and tuberculosis was established long ago, when ancient societies sent people with TB into the sunlight for therapy. Increasing vitamin D levels is known to wake up cells and trigger an immune response whenever infection or inflammation is present.

Also well established is the use of the TB vaccine to treat several forms of bladder cancer. The vaccine works by pushing the body’s immune system to fight the cancer cells. However, approximately 30 to 40 percent of people with bladder cancer who receive the vaccine do not respond to it.

Lee is investigating whether a lack of vitamin D in these patients might explain the poor response.

Prior studies have shown that BCG, the modified bacteria that causes TB, turns on a toll-like receptor signal that makes more vitamin D receptors and induces a key enzyme that converts to the most potent, bioactive form of vitamin D, or 1,25-hydroxylvitamin D3. So Lee thought it was likely that boosting the levels of vitamin D in the body would activate this process, enhancing the vaccine.

The mouse study involved four arms: a control group, a group that received vitamin D treatment alone, a group that received BCG treatment alone, and a fourth group that received the combination of vitamin D and the BCG vaccine. The latter (combination therapy) group was the only group in which 100 percent survived bladder cancer, Lee said.

“Vitamin D appears to be critical to the success of BCG immunotherapy,” Lee said, although she does not advise taking high doses of vitamin D unless under medical supervision. “Just as importantly, though, we have shown the migration and signaling involved in establishing vitamin D as a biomarker that can be easily measured.”

Oral Vitamin D Supplements Fight Prostate Cancer

Higher oral doses of plain vitamin D raised levels of calcitriol in prostate tissue. Higher prostate levels of calcitriol, a hormone made from vitamin D, corresponded with lower levels of the proliferation marker Ki67 and increased levels of cancer growth-inhibitory microRNAs in prostate cancer cells.

The results not only point to the mechanisms by which vitamin D affects the rate of prostate cancer growth, but also indicate that vitamin D may slow the growth of prostate cancer cells — a key finding given that the role of vitamin D in prostate cancer has been “controversial, with some suggesting that higher levels of vitamin D should be avoided,” said Reinhold Vieth, Ph.D., professor at the University of Toronto in Toronto, Ontario, Canada.

“This study shows calcitriol makes the foot come off the gas pedal of cancer growth. We are not able to prove that the speed of the car has slowed down, but it certainly is a good sign,” said Vieth. “We expect that this early-phase clinical trial will open the door for more detailed clinical research into the usefulness of vitamin D in the treatment or prevention of prostate cancer.”

Vieth and colleagues previously reported that in men who were being monitored regularly for prostate cancer, higher vitamin D levels slowed the rate of rise in prostate-specific antigen levels. They randomly assigned 66 men scheduled for radical prostatectomy to daily vitamin D in doses of 400, 10,000 or 40,000 IU for three to eight weeks before surgery. Researchers found that calcitriol levels in the prostate increased progressively with each daily dose of vitamin D, with 40,000 IU showing the highest levels. These higher levels of calcitriol corresponded with lower prostate levels of Ki67, a protein that indicates prostate cancer cell growth, as well as higher levels of specific growth-inhibitory microRNAs.

Vieth stressed that he and his colleagues do not advocate vitamin D supplementation in doses higher than 4,000 IU daily. Patients were assigned to the 40,000 IU daily dose because of the short presurgical time frame available for study, not as a regular regimen.

“Plain vitamin D provides the raw material to permit the body to take care of its own needs,” he said. “We showed here that plain vitamin D allows the prostate to regulate its own level of calcitriol, and at the doses we used, for the time frame we used, it has been safe with the hoped-for desirable outcomes.”

The next step in this line of research will be to conduct a phase III clinical trial in which men who are being monitored for prostate cancer progression will be randomly assigned to placebo or to a “high” dose of plain vitamin D.

Robot Assisted Prostate Cancer Surgery Compares Favorably

Outcomes from use of a robot to assist surgeons in removal of a cancerous prostate are at least as good, if not better, than the other two techniques used for a radical prostatectomy -- open or laparoscopic surgery -- according to a large meta analysis led by researchers at NewYork-Presbyterian/Weill Cornell.

The study, published February 24 online in European Urology, should help resolve some of the controversy regarding use of the robotic option, known as robot assisted laparoscopic radical prostatectomy (RALP), says the study's lead author, Dr. Ashutosh Tewari, director of the Lefrak Center for Robotic Surgery and director of the Prostate Cancer Institute at New York-Presbyterian Hospital/Weill Cornell Medical Center.

"There is a lot of debate about the best way to remove a cancerous prostate gland," says Dr. Tewari, who is also the Ronald P. Lynch Professor of Urologic Oncology and professor of urology and public health at Weill Cornell Medical College. "Since the robotic technology is expensive, the patient benefits often get intertwined with the societal costs. It is clear, however, that robotic surgery is the most popular surgical modality today. This study represents the largest ever systematic review of patient outcomes comparing robotic-assisted, laparoscopic and open radical prostatectomy.

By analyzing 400 original research articles -- all that have been published to date on the three methods -- Dr. Tewari and his colleagues concluded that RALP is more effective than a pure laparoscopic approach and comparable to an open surgical approach in completely removing cancer from the body. Positive surgical margins, a measure of oncological efficacy, were lower in patients receiving robotic radical prostatectomy as compared to those undergoing laparoscopic prostatectomy.

The researchers also found that robot assisted surgery had fewer intraoperative and perioperative complication rates when compared to both laparoscopic and open approaches. In addition, robotic showed both less intraoperative blood loss and less blood transfusions as compared to open surgery.

The meta analysis included treatment information on 286,876 patients, representing the largest compilation of radical prostatectomy patients to date.

"Understanding the best method to remove the prostate matters," Dr. Tewari says, "because prostate cancer is the most common diagnosed cancer and the second most common cause of cancer death for men in developed countries."

But given the nature of the study, Dr. Tewari says he cannot recommend one surgical approach over another. He emphasizes that surgical approaches need to be adjusted for the technique and experience of the surgeon. Many studies have shown that surgical experience is an independent predictor for outcomes, far beyond the approach alone.

"This paper is innovative in its attempt to unpack the outcomes data, in a systematic way, surrounding the three surgical modalities for prostate cancer treatment, but the data we used were not standardized -- outcome measures differed between studies," he says. "Still I believe the results are meaningful in that it shows RALP has at least as good outcomes as the other methods."

Challenges of Randomized Studies for Prostate Surgery

The three forms of surgery studied are "open radical" in which the prostate is removed via an abdominal incision in the belly button or pubic bone; laparoscopic prostatectomy that requires several small minimally invasive "keyhole" incisions in the abdomen, and robotic surgery, which is a form of laparoscopic surgery. RALP is done through keyholes with the aid of robotic arms that eliminate hand tremor as well as advanced optics that magnify the prostate and surrounding nerves in three-dimensions.

"It is hard to accrue patients for randomized studies. We have an ongoing study open at our institution, investigating the quality of life differences between robotic and open radical prostatectomy. This is designed as a randomized controlled study," he says. "But no one has enrolled because they did not want to be randomized to a treatment they don't prefer. Patients often come, especially to prostate cancer specialists, self-selecting for a particular treatment modality."

So Dr. Tewari and Peter Wiklund, M.D., of Sweden's Karolinska University Hospital, developed a study that examined all of the peer-reviewed studies published on any of the three techniques.

This ambitious effort was aimed at understanding the short-term (30 day) outcomes of the three surgical techniques. Given the short time frame, the meta analysis did not compare outcomes for urinary continence or sexual potency.

The researchers determined that complications and mortality were low for all three methods, suggesting that radical prostatectomy is a safe procedure.

Significant differences found were in the lower positive surgical margin (PSM) rates for RALP compared with laparoscopic surgery and lower intra operative and perioperative complications for RALP in comparison to other modalities. "PSM rates are important because they represent the effectiveness by which cancer is removed," Dr. Tewari says. "The RALP PSM rate was as good as open surgery," he adds.

The researchers also found that both laparoscopic and robotic surgery patients experienced lower rates of blood loss and transfusions and a shorter hospital stay compared with patients who had traditional surgery. Other measures, such as rates of readmission, reoperation, and complications, seemed to favor RALP, the researchers say.

"We would love to be able to directly compare the three prostatectomy surgical techniques, but that may not happen," Dr. Tewari says. "This study is the first to provide an important -- and much needed -- analysis of the short term benefits and risks between curative surgeries that many men rely on."

Oregano Kills Prostate Cancer Cells

Oregano, the common pizza and pasta seasoning herb, has long been known to possess a variety of beneficial health effects, but a new study by researchers at Long Island University (LIU) indicates that an ingredient of this spice could potentially be used to treat prostate cancer, the second leading cause of cancer death in American men.

Prostate cancer is a type of cancer that starts in the prostate gland and usually occurs in older men. Recent data shows that about 1 in 36 men will die of prostate cancer. Estimated new cases and deaths from this disease condition in the US in 2012 alone are 241,740 and 28,170, respectively. Current treatment options for patients include surgery, radiation therapy, hormone therapy, chemotherapy, and immune therapy. Unfortunately, these are associated with considerable complications and/or severe side effects.

Dr. Supriya Bavadekar, PhD, RPh, Assistant Professor of Pharmacology at LIU's Arnold & Marie Schwartz College of Pharmacy and Health Sciences, is currently testing carvacrol, a constituent of oregano, on prostate cancer cells. The results of her study demonstrate that the compound induces apoptosis in these cells. Apoptosis, Dr. Bavadekar explains, is programmed cell death, or simply "cell suicide." Dr. Bavadekar and her group are presently trying to determine the signaling pathways that the compound employs to bring about cancer cell suicide.

"We know that oregano possesses anti-bacterial as well as anti-inflammatory properties, but its effects on cancer cells really elevate the spice to the level of a super-spice like turmeric," said Dr. Bavadekar. Though the study is at its preliminary stage, she believes that the initial data indicates a huge potential in terms of carvacrol's use as an anti-cancer agent. "A significant advantage is that oregano is commonly used in food and has a 'Generally Recognized As Safe' status in the US. We expect this to translate into a decreased risk of severe toxic effects."

"Some researchers have previously shown that eating pizza may cut down cancer risk. This effect has been mostly attributed to lycopene, a substance found in tomato sauce, but we now feel that even the oregano seasoning may play a role," stated Dr. Bavadekar. "If the study continues to yield positive results, this super-spice may represent a very promising therapy for patients with prostate cancer."