Testosterone (androgen)-depleting therapies are usually the first line of defense for men with newly-diagnosed or recurrent prostate cancer. But resistance to these therapies develop over time which leaves the patient and physicians with a number of choices as to the next sequence of therapies to be administered. Recently, guidelines, issued jointly by the American Society of Clinical Oncology (ASCO) and Cancer Care Ontario (CCO) in Canada, highlight recent advances in treating this more advanced form of prostate cancer. Six new treatments have been approved in the last two years for the treatment of prostate cancer and its symptoms. However, opinions differ as to the sequence of using these therapies and their cost, their relationships to a man’s quality of life, the disease stage of the cancer, and prior therapies received by the patient. Combination studies are certainly needed and underway. The new guidelines for hormone therapy – resistant tumors that have metastasized are based on a review of 56 randomized clinical trials published since 1979 and include the following recommendations.
a) Continue hormone-deprivation therapy indefinitely. b) In addition to hormone deprivation, offer patients one of three treatment options including Zytiga® (abiraterone acetate and prednisone), Xtandi® (enzalutamide), or alpha-radin (radium-223 chloride if the cancer has spread to the bones). All three treatments are associated with improved survival, quality of life and a favorable balance of benefit and harms. c) When considering chemotherapy, taxotere (docetaxel®) with prednisone should be an option but side effects must be discussed. See also the September 20th, 2014 blog. d) Offer cabazitaxel to men whose disease worsens even if taxotere has been tried, but again discuss the side effects. e) Offer Provenge® (sipuleucel-T) to men with no or minimal cancer symptoms. Some physicians maintain that it can be most effective to initially stimulate the immune system with agents like Provenge® before other agents are utilized. f) Offer mitoxantrone but include a discussion of the drug’s limited clinical benefit and side effect risk. Mitoxantrone is also used to treat leukemias and multiple sclerosis. g) Offer ketoconazole or the anti-androgen therapies bicalutamide, flutamide or nilutamide but discuss the limited clinical benefits of these three medications. h) Do not offer other anti-cancer drugs such as bevacizumab (Avastin®), estramustine or sunitinib. i) Begin discussions of palliative care early on while discussing treatment options.
The experts on the panel formulating these guidelines said the optimum sequence in which various treatments should be given remains unclear, but “ongoing clinical trials are exploring this question, as well as potential benefits of combining various treatments.”
An article published in the January 4th, 2014 issue of the journal European Urology reported the outcome of a Swiss trial involving men with hormone-resistant (refractory) prostate cancer (defined as a testosterone level of less than 50 ng/dL with progressive disease) who were given the anti-diabetic drug metformin. For the trial, 44 non-diabetic men who had not been treated with chemotherapy for progressive, metastatic hormone-resistant prostate cancer causing few or no symptoms were given 1,000 mg (one gram) of metformin twice a day until disease progression. Assessment of disease status- included computer tomography of the abdomen, pelvis and chest, bone scanning and serum prostate cancer-specific antigen (PSA) level measurement- was conducted every 12 weeks. After initiation of metformin therapy, 36% of the group was progression-free at 12 weeks and 9% were still progression-free at 24 weeks. PSA doubling time, a measure of disease progression, was beneficially prolonged in 52% of patients after the initiation of metformin. It should be noted that metformin is also associated with improved insulin sensitivity. It should be administered only under a physician’s approval, care and control.
In an online April 18th, 2014 publication in the journal Cancer Epidemiology, Biomarkers and Prevention, Johns Hopkins researchers reveal a link between chronic inflammation and a greater risk of high-grade prostate cancer. The study included 191 men with prostate cancer and 209 controls without the disease who received a placebo in the Prostate Cancer Prevention Trial, which evaluated the effect of the drug finasteride on prostate cancer prevention. Biopsies conducted at the end of the study provided information on the presence of inflammation in benign prostate tissue. Among men who had inflammation in one or more of the biopsy cores, there was a 78% higher risk of having prostate cancer and more than twice the risk of aggressive disease in comparison with men who had no cores indicating inflammation. This observational study reveals an association between prostate inflammation and prostate cancer, although it is not proof that inflammation is the cause of prostate cancer.
A recent study published in Clinical Cancer Research, (May 1, 2014; 20; 2289-99) indicated that men at risk of prostate cancer are more likely to develop an aggressive form of the disease if they are deficient in vitamin D. University of Illinois – Chicago and Northwestern University researchers examined data from 667 men aged 40 to 79 who had elevated PSA levels or other prostate cancer risks. The men were screened for vitamin D levels. In general, normal blood levels of 25-hydroxyvitamin D range from 30-80 ng/mL. Typical values for men in the study were under 20 ng/mL. About 44% of men with positive biopsies had low vitamin D levels. Among the men who had a positive cancer biopsy, those with very low vitamin D levels (under 12 ng/mL) had greater odds of more advanced and aggressive cancers than those with normal levels. The lower the vitamin D level, the greater the risk. It should be noted that while 25-hydroxyvitamin D is known to impact growth of both benign and malignant prostate cells, this is the first study to link vitamin D deficiency and biopsy outcomes in high-risk men. The authors note that “vitamin D deficiency could be a biomarker of advanced prostate tumor progression in large segments of the general population”, however, more research is needed. But it would be wise for men to be screened for vitamin D deficiency using the 25-hydroxyvitamin blood test and treated if needed.
1) A recent article was published from the Washington University School of Medicine which compared the results of prostate cancer biopsies as guided by magnetic resonance imaging (MRI) with those obtained via ultrasound guidance. It was concluded that MRI-guided biopsies were more likely to find aggressive tumors than those that rely on ultrasound. For specific details, see the following link.
2) Another article published in Medline Plus, described a Duke University study of the effects of diet and lifestyle on prostate cancer. A diet rich in complex carbohydrates and lower in protein and fat is associated with a 60 percent to 70 percent reduced risk of prostate cancer according to the researchers. In addition, a fiber-filled diet reduced the risk of aggressive prostate cancer by 70 percent to 80 percent. The presence of metabolic syndrome factors also increased the cancer risk. Metabolic syndrome consists of a group of risk factors that increase a person’s risk of heart disease, diabetes and stroke. They include obesity, high blood pressure, elevated blood sugar levels, elevated levels of triglycerides (blood fats) and reduced levels of “good” HDL cholesterol.
3) Lastly, Columbia University researchers have identified two genes that they claim “are likely driving the most aggressive cases of prostate cancer. Other scientists had linked the genes, FOXM1 and CENPF, to cancer, but had not connected them to prostate growths. And more importantly, it was observed that the two genes’ cancer-causing effects only occurred if they are turned on at the same time. These two genes individually don’t do anything, or very little, but only when they are co-active do they produce aggressive forms of the disease.” The presence of activity in these two genes could be determined at the time of a biopsy. “If both genes are turned on and highly active, then men would be advised to get immediate treatment such as surgery, radiation or tumor-targeting drugs, or some combination of these. If neither gene, or only one is active, then doctors might recommend less intensive therapy while they monitored the tumors” according to the researchers.
Prostate biopsies performed using magnetic resonance imaging (MRI) are more likely to find aggressive tumors than those that rely on ultrasound, – See more at: http://www.siteman.wustl.edu/ContentPage.aspx?id=8115#sthash.ExKA8YfO.dpuf
The Johns Hopkins Health Alerts are extremely informative about various health issues including prostate cancer. The latest alert (June 14th) discussed the Gleason Score, the most important factor in predicting the current state of a prostate cancer. The Gleason Score is based on tumor grade, which is an indication of the tumor’s aggressiveness. The tumor grade reflects how far the cancer cells deviate from normal healthy cells. See the link for the full article.
Several articles of interest were recently published in the February-March, 2014 NewsPulse from the Prostate Cancer Foundation (PCF). This information had been presented at the American Association for Cancer Research (AACR) meeting. The first article described the benefits of exercise in men prior to their prostate cancer diagnosis as well as during therapy for their condition. A second article cited a new study involving 1700 men who received a new, oral hormone therapy drug, enzalutamide. The treatment increased survival by 29% and delayed disease progression by 81% in men with advanced prostate cancer who had become resistant to standard hormonal therapies and who had not received previous chemotherapy. In 2012, the U.S. Food and Drug Administration had approved enzalutamide for use in prostate cancer patients who had received prior chemotherapy. Enzalutamide is a type of hormonal therapy that blocks the androgen (male hormone) receptor on cells. In addition, treatment with enzalutamide delayed the need for chemotherapy by 17 months. A third article described how combining clinical information from the CAPRA score with the genetic information expressed in either of the Oncotype DX or Prolaris assays yielded improved prostate cancer risk assessment and reduced overtreatment. These results were better than results achieved with either clinical or genetic information alone. A CAPRA score is a means to predict whether a patient has low, intermediate, or high risk prostate cancer; the scores generated are used to guide treatment decisions. CAPRA scores integrate PSA levels, Gleason score, clinical T stage, patient age, and the percentage of prostate biopsy tissue containing malignant cells. This methodology is 80% accurate in predicting the likelihood of progression to fatal disease.
A multi-center study from the Fred Hutchinson Cancer Center in Seattle and published in the Journal of the National Cancer Institute have shown that vitamin E can heighten the risk in men with low baseline selenium levels. In addition, selenium supplements can raise the prostate cancer risk in men with high baseline levels of the trace element. The researchers concluded that their study showed no benefits to any man from either selenium or vitamin E supplements and for a significant number of men, these supplements were actually harmful. For more details, see the following link.
1) Intermittent Hormonal Therapy: Prostate cancer is often kept “under control” by depriving the cancer cells of their “fuel”, namely androgens such as testosterone or dihydrotestosterone. Androgen deprivation (hormonal) therapy (ADT) is often applied on an intermittent basis the goal of which is to minimize potentially harmful side effects. The May 11th edition of the Johns Hopkins Prostate Disorders Health Alerts contained an excellent overview of intermittent androgen suppression.
2) Why Androgen Deprivation Enhances Radiation Therapy: It has been known since 2011 that adding a short course of androgen deprivation therapy (ADT) to radiation therapy in prostate cancer patients increased their chances for survival. Recent research indicates that the rationale for this combination treatment lies in the fact that ADT retards the ability of cancer cells to repair DNA damage caused by the radiation therapy thus leading to their programmed cell death or apoptosis. One such DNA repair enzyme is called DNAPK which may be a good target for antitumor drug development. Inhibitors of a similar single-strand DNA repair enzyme, PARP1 [(polyADP-ribose) polymerase], are currently being evaluated in Phase III clinical trials involving breast and ovarian cancers. (PARP1 inhibitors seem to have a beneficial effect on women with a specific BRCA breast cancer genetic mutation.) The relationship between the androgen receptor (AR) and DNA repair proteins such as DNAPK is also summarized in the March 31st issue of the Prostate Cancer Foundation (PCF) NewsPulse.
3) A Study Comparing “Watchful Waiting” versus Surgery in Younger Prostate Cancer Patients: A joint Swedish – Harvard life expectancy study of 700 men with early prostate cancer and published in the March 6th New England Journal of Medicine concluded that surgery (radical prostatectomy) may “trump” watchful waiting in younger men diagnosed with prostate cancer. A summary of this study and comments by other researchers was published in the March 31st issue of the Prostate Cancer Foundation (PCF) NewsPulse.
4) The Effects of Statin Drugs On Prostate Cancer: The March 31st PCF NewsPulse also contained a review of various studies related to the effects of cholesterol-lowering statin drugs on prostate cancer. Researchers conclude that statins do not have an effect on the incidence of prostate cancer however prolonged use may lower the risk of advanced disease and death. No protective effects from statins have been observed and there does not seem to be any association between statin use and early incidence of prostate cancer. Current research is focused on where statins may play a role in the overall prostate cancer cycle.
The Prostate Cancer Research Institute publishes a monthly periodical called “Insights”. At the end of 2013, they also updated their user-friendly and searchable website, http://www.pcri.org. The February 2014 issue of Insights contained considerable information which I will briefly summarize. I encourage you to see the articles in their entirety.
First, Dr. John Davis from MD Anderson Cancer Center describes the “Prolaris Test for Prostate Cancer” which serves as an introduction to this novel genomic test and its role in improving clinical decisions about treating prostate cancer. Prolaris is a test performed on biopsy tissue that looks at the average expression of 31 Cell Cycle Progression (CCP) Genes, which are involved in telling a cell to divide in two. Such a test result can be grouped with other factors to help determine the potential prostate cancer aggressiveness or lack thereof. The test can be helpful in men who are interested in active surveillance but may not have low-grade, low-volume disease. It can help define the risk of cancer-related mortality if left untreated. The test is expensive (around $3400) and insurance coverage can vary.
Secondly, an article by Dr. Mark Scholz summarizes presentation highlights from a recent Prostate Cancer Foundation retreat. One presentation described the discovery of a new gene product called SCHLAP-1 that can help predict the likelihood of future metastases. SCHLAP-1 may have the same predictive power as a Gleason score in distinguishing low-grade from high-grade disease. Another presentation discussed the role of PSA decline as a measure of treatment effectiveness. PSA can be notably inaccurate as demonstrated with Provenge and Xofigo as neither causes a consistent decline in PSA though both have been shown to improve survival. Dr. Howard Scher of Sloan-Kettering described studies that rely on measuring a decline in circulating tumor cells (CTC) in response to therapy as an accurate method for early prediction of long-term survival. Dr. Scher combines CTC levels with measurement of an enzyme called lactate dehydrogenase (LDH) to differentiate patients into low, intermediate or high risk categories. The system has been tested and validated to predict survival and could be used by the FDA for evaluating new drugs according to Dr. Scher. Dr. Victor Velculescu from Johns Hopkins presented his work which suggests that the presence or absence of microscopic residual disease (micro-metastases) could be detected with new genetic tests called genomic analysis. If a test could confirm that a patient was free of metastases, then long-term hormonal treatment might be unnecessary.
An effect called the Abscopal Effect states that radiation may actually stimulate one’s immune system according to Dr. Mark Scholz. Presently, little is known about how anti-cancer therapies such as radiation interact with immunotherapy in a clinical setting. Phoenix, AZ – based 21st Century Oncology is beginning a clinical trial designed to determine if radiation-induced tumor death augments the anti-tumor responses from Provenge. Patients treated with a combination of spot radiation and Provenge will have their tumor responses tracked with C11-acetate PET scans. See the article for details.
In an article named “A New Approach to Prostate Cancer Screening”, the authors suggest that “rather than doing an immediate biopsy, doctors should consider prostate imaging with multi-parametric MRI or Color Doppler Ultrasound. In experienced hands with state-of-the-art equipment, high grade cancer can be ruled out with 95 to 98% accuracy. And when imaging detects a high-grade lesion, a targeted biopsy directed specifically at the area of abnormality can be performed. If the scans show that no high-grade disease is present, the patient can forgo biopsy and simply monitor the situation with further PSA testing and, if necessary, consider additional imaging in six to twelve months.” The same issue contains an article called “What’s New in Prostate Cancer” by Dr. Stanley Brosman. He discusses the use of multi-parametric-MRI (mp-MRI) to see abnormalities suspicious for prostate cancer. mp-MRI does tend to miss cancers that are low-grade which may be a good thing. In experienced hands, the ability to detect Gleason score 7 or 8 tumors was 98% accurate and the ability to predict the absence of aggressive tumors was 91%. This technique also allows for a more targeted approach to doing a needle biopsy. The mp-MRI is also very useful for following prostate cancer patients who are on Active Surveillance. A drawback is that a specific type of MRI, namely a 3-Tesla MRI, is needed in the hands of a highly trained radiologist. The test is also currently expensive and may not be covered by all types of insurance.
Finally, medications to treat osteoporosis in men receiving hormone therapy have been widely used for years. It has now been learned that men who have bone metastases can have stabilization and regression of the tumor with the use of these agents. Denosumab (Prolia) and XGEVA are being used with good results. It was reported that the use of Denosumab (Prolia) may be a preventive agent and delay the onset of bone metastases in high-risk patients.