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It would be useful if one could detect and identify the location of localized prostate cancer recurrences and metastatic disease in early PSA recurrence in men who had previously failed initial cancer treatments. For example, such identified “focal” or local recurrences in 1-2 specific areas of the body could then be treated surgically or with targeted radiation. These areas of recurrence might not have been detectable by bone, CT or other scanning methods alone. Physicians at the Mayo Clinic in Rochester, Minnesota and at the Arizona Molecular Imaging Center in Phoenix, Arizona describe the use of positron emission tomography (PET)/CT scanning to identify such localized areas of recurrent prostate cancer in men who have failed surgery, radiation, hormonal and/or chemotherapies. The specific tumor-targeting agents are C-11 choline and C-11 acetate administered intravenously. These radioactive agents emit positrons (positively-charged electrons) over a short period of time; their half-life is about 20 minutes. Therefore, the agents have to be prepared in an on-site cyclotron just prior to their use. In preliminary results reported in the August, 2012 issue of the Prostate Cancer Research Institute (PCRI)Insights, Arizona researchers report an overall detection rate of  85% for recurrent or metastatic disease using C-11 acetate PET/CT imaging. Detection was followed by radiation therapy or surgical removal of the identified lesion. Access to C-11 acetate requires participation in an approved clinical study. For information about participating in this on-going Phase II clinical trial see the ClinicalTrials.gov website at http://clinicaltrials.gov/ct2/show/record/NCT01304485.  The C-11 choline agent available at the Mayo Clinic has already been approved by the Food and Drug Administration (FDA) as an agent for prostate cancer imaging. It has demonstrated accuracy in detecting lesions in both bone and lymph nodes. Examples of its usefulness are provided in a 17-minute video presentation given by Mayo’s principal investigator, Dr. Eugene Kwon. Both of these studies are relatively small in scope. The usefulness of this technique rests on its ability to identify the specific location of localized cancer recurrences and then the ability to treat them surgically or with radiation. The PET/CT imaging therapy described above would not be applicable to systemic disease covering multiple areas of the body. Its value would be in cases where recurrent tumors / metastases could be identified and localized in a specific area of the body which would allow the tumors to be removed surgically or with radiation.

While PET/CT imaging is not currently widely accessible, it may be very useful in specific cases. On a personal note, I know of a prostate cancer patient who might well have benefitted from the techniques described above. He had undergone a seemingly-successful radical prostatectomy. His PSA remained undetectable for about eight (8) years. Shortly thereafter, he began to experience a strong pain in his lower back / spinal area. X-rays, bone and CT scans were inconclusive in determining the origin of his pain. Meanwhile, his PSA escalated very rapidly to 25 ng/dL. An MRI revealed a mass in his lower back/spine which was removed surgically within two days of diagnosis. The patient’s PSA has been undetectable for the last two years.

The American Society of Clinical Oncology (ASCO) is a highly respected organization. On July 16th 2012, a committee of experts from ASCO published a provisional clinical opinion regarding PSA screening in the Journal of Clinical Oncology. This information is also summarized in the July 24th, 2012 issue of the National Cancer Institute (NCI) Bulletin. Briefly, ASCO experts concluded that for men with a life expectancy of 10 years or less,  “it is recommended that general screening for prostate cancer with total PSA be discouraged, because harms seem to outweigh potential benefits.” However, for men with life expectancies of greater than ten (10) years, “it is recommended that physicians discuss with their patients whether PSA testing for prostate cancer screening is appropriate for them. PSA testing may save lives but is associated with harms, including complications, from unnecessary biopsy, surgery, or radiation treatment.” Thus younger men may have meaningful benefits from PSA screening but this can be accompanied by a risk of harms. These aspects must be balanced in order to arrive at a plan of action if warranted.

 

 

Since its October, 2011 initial advisory, and after receiving input from the medical community including many leading urologists and oncologists, the United States Preventative Services Task Force (USPSTF) recently issued its final recommendation against screening asymptomatic men for prostate cancer using the prostate-specific antigen (PSA) test.  (An earlier 2008 recommendation had advised against screening men over the age of 75.)  The USPSTF conclusions are discussed in the May 29th, 2012 issue of the National Cancer Institute Bulletin among other sites below. The USPSTF panel concluded that routine diagnostic PSA screening could not be clearly demonstrated to save lives and its potentially-significant harms (such as false positive results, biopsy-related infections, potential incontinence and erectile dysfunction) outweigh any small potential benefits. However, PSA testing will still be used to monitor progression of prostate cancer after its diagnosis or treatment. Medicare is expected to continue to pay for such PSA evaluations. It must be noted that the USPSTF did not include any urologists nor medical oncologists on their panel. For a full listing of the Task Force members, their affiliations and their specific fields of expertise see http://www.uspreventiveservicestaskforce.org/members.htm.  Strong criticisms of this recommendation have been issued by noted American urologists as well as medical and professional organizations such as the American Urological Association and the National Comprehensive Cancer Network.  Additionally, a dissenting opinion was published in the Annals of Internal Medicine by some of the leading clinical scholars in prostate cancer care, including Dr. William Catalona, Medical Director of the Urological Research Foundation and Dr. Patrick C. Walsh, University Distinguished Service Professor of Urology at Johns Hopkins. These experts believe the USPSTF overestimated the harms and underestimated the benefits of PSA screening in the United States.  Much of the discussion centered upon two separate clinical trials; the National Cancer Institute (NCI)-funded Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial and the European Randomized Study of Screening for Prostate Cancer (ERSPC). A recent study involving 20,000 Swedish men over a 14-year period has been cited as strong evidence that PSA screening does indeed save lives. (See the May 29th issue of the ZeroHour Newsletter).  For an overview of affirming and dissenting opinions from various groups, see the Prostate Cancer Research Institute (PCRI) Weekly for May 30th, or the May, 2012 PCRI NewsPulse.

In light of these new recommendations, what should a man do at this point? The most important need is a shared decision-making process between a man and his trusted physician. Individual patient factors such as age, medical condition, symptoms (or lack thereof), family history, ethnicity or concerns about prostate cancer must form the basis of a rational decision between a patient and his physician to undergo PSA testing.  As stated in the Prostate Cancer Foundation Newsletter, “the USPSTF’s position provides a teachable and actionable moment for the medical community to improve targeting of PSA screening in patients, reduce over-testing and improve processes of patient education on the risks of overtreatment from PSA screening.”  See also the June 2012 edition of Prostate Cancer Advances, “PSA: Better Patient Education.”

Finally, targeted screening using specific biomarkers is urgently needed to identify and differentiate between aggressive cancers requiring treatment and those best followed by “active surveillance”. Examples of such biomarkers include a urine test to identify abnormally high levels of genetic RNA made from the PCA3 gene in prostate cancer cells. This urine test commercialized by Gen-Probe and known as PROGENSA PCA3, was approved by the Food and Drug Administration (FDA) in February of this year. A National Cancer Institute (NCI) study examined the predictive value of using PROGENSA PCA3 to detect prostate cancer. A positive PCA3 test predicted a positive biopsy of 80 percent of the time at initial biopsy; and, for men undergoing repeat biopsies, a negative urine test predicted a negative biopsy 88 percent of the time.

Still another example of a potential biomarker being studied at Cornell, MIT and Harvard Universities is the identification of mutations in a gene called SPOP. Such genetic alterations may be unique to early stage prostate cancer. These are just two examples of potential targeted screens which hopefully will one day replace the PSA test to provide more precise information to guide physicians and their patients in their diagnoses and possible treatments if necessary.

Two articles discussing the development of new genetic tests which could potentially be used to detect and determine aggressive prostate cancers were published in the May 2nd and May 15th  issues of the Zerohour Newsletter of the Project to End Prostate Cancer.

The biggest problem facing men who have been diagnosed with prostate cancer is to determine whether the cancer is potentially aggressive and therefore requires treatment or whether it can be subject to “active surveillance”. PSA values alone will not answer this question. However, genetic changes or biomarkers are being actively sought by researchers to help determine the aggressive nature of the cancer. Three such genes are named ERG, ETV1 and PTEN. Researchers at Stanford University and Abbott Molecular are working to develop a molecular assay to detect rearrangements of the ERG and ETV1 genes and measure loss of the PTEN gene. A study published in the British Journal of Cancer evaluated 308 prostate cancer patients who were treated conservatively. “Those who did not show abnormal ERG/ETV1 genetic changes with no PTEN gene loss had excellent prognosis, as evidenced by an 85 percent survival rate after 11 years. Men who showed PTEN gene loss in the absence of the gene rearrangements had a poor survival rate of 13.7 percent. The study showed the promise of the new biomarkers to identify patients who would benefit most from intensive therapies.”

In another study, researchers at the Mayo Clinic have found that changes to the “on-off” switches of genes occur early in the development of prostate cancer and could be used as biomarkers to detect the disease months or even years earlier than current approaches. “These biomarkers — known as DNA methylation profiles — also can predict if the cancer is going to recur and if that recurrence will remain localized to the prostate or, instead, spread to other organs. The study, published in the journal Clinical Cancer Research, is the first to evaluate the methylation changes that occur across the entire human genome in prostate cancer. The discovery could someday help physicians diagnose prostate cancer earlier and make more effective treatment decisions to improve cure rates and reduce deaths. It also points to the development of new drugs that reverse the DNA methylation changes, turning the “off” switch back “on” and returning the genetic code to its normal, noncancerous state.”