Update on prostate cancer screening guidelines

– Welcome to our Cancer Care Symposium. I have been asked to discuss prostate cancer screening, which will primarily focus on the evolving role of PSA. Prostate cancer is the second most frequently diagnosed cancer, and the third most common cause of cancer death in US men. There are approximately 192,000 cases, as of 2018, a year. US men have a 12% lifetime risk of developing prostate cancer, and a 2.4% risk of dying of a disease. There has been declining mortality in prostate cancer from 1992 to 2016. The reasons are not entirely clear, but likely have to do with both PSA as well as improvements in treatment. The objectives for this particular talk are as follows. One, define the prostate-specific antigen, parentheses PSA, actually is, and describe the history of its discovery as a use as a biomarker. Learn the application of the PSA and its derivatives in predicting prostate cancer. And finally, recognize and interpret some national guidelines for prostate cancer, including the National Collaborative Cancer Center Network. The United States Preventative Task Force, and the American Cancer Society guidelines. What is prostate-specific antigen? There is a picture of it in a three dimensional diagram from days as a chem major, but it is a glycoprotein, protease, found in high concentrations in the male ejaculate. Its early discovery was pioneered by forensic scientists looking for a tool to use in rape cases. It is in the ejaculate and independent of semen, so it can be used in azoospermic males as well as in men who have undergone vasectomies. Contemporaneously, it was also being looked at as a novel birth control agent target, as the role of PSA in the ejaculate is to liquefy coagulum, such that the sperm are free to swim and implant the egg. It does this by its protease activity, which is activated by a lowered pH in the vaginal environment. Zinc also plays a role in its regulation. It wasn’t until nearly two decades after its discovery that was first reported in the New England Journal of Medicine, it’s used as a biomarker in prostate cancer. This sentinel article published in the New England Journal of Medicine in 1987 presents the data of men that they reviewed with prostate cancer. It evaluated both PSAs, as well as serum prostatic acid phosphatase, which at the time was the gold standard for monitoring prostate cancer. In men with a known diagnosis of prostate cancer, the levels of PAP and PSA were evaluated and reviewed. PSA was found to be elevated in 122 of 127 newly-diagnosed prostate cancer patients. Seven of those 12 had very early stage disease. PAP, the previous gold standard, was only elevated in 57 of 127 patients. In addition, PSA seemed to correlate well with both clinical stage, as well as the amount of tumor. PSA was seen to decline to undetectable after successful surgery with an in-vivo half-life of two and a half days, whereas prostatic acid phosphatase, the previous standard, did not become zero after surgery. After this sentinel study, PSA started to be evaluated and used for both monitoring and ultimately screening for prostate cancer. So you might ask how does this glycoprotein produced in the prostate measured in the blood help in determining someone’s risk for prostate cancer? Well PSA is normally found at high concentrations in the prostate and ejaculate. In a healthy prostate, the integrity of the prostate gland itself keeps most of the PSA in the gland. Only small amounts of the glycoproteins end up in the blood. These small amounts are normal. Conditions which interrupt the gland’s integrity can lead to high leakage of the PSA in the blood. Conditions such as cancer, and benign conditions, such as infection, or benign prostatic hypertrophy can elevate the levels in the blood. Some very undifferentiated tumors or cancers fail to produce PSA. As we have learned, the PSA is normally found in low levels in blood. And what is meant by normal can vary. It varies by several factors, the most important being age, but also to a lesser extent race. Normal PSA ranges from zero to 2.5 in the fourth decade, and increases to our upper normal of 6.5 in the seventh decade. It seems that race somewhat plays a role in that normal numbers are lower for Asian-Americans, intermediate for Caucasian, and somewhat higher for African-Americans. However, it’s not a huge difference, but African-Americans’ normal range limit tends to be about a point higher. As PSA adaptation has increased, derivatives of the value have become helpful in predicting prostate cancer detection. The two derivatives that you will see most often reported are PSA velocity, and free PSA. PSA velocity is merely the rise of baseline PSA over time. A PSA short doubling time measured in months is associated with an increased risk of cancer detection. Free PSA, that percentage of total PSA, which is not bound to protein in the blood, is known as free PSA. PSA which is bound to protein in the blood is more likely to be associated with cancer than that, and the ratio is high. This is particularly helpful in PSA reading, which is only modestly elevated, or higher than normal to help determine the likelihood of cancer. This slide shows that free PSA can be particularly helpful in younger men as seen in this slide. The probability of a very low free PSA in different age groups is most pronounced as a predictive measure in younger men, as can be seen. Finding a more treatable cancer in younger patients obviously will yield the largest benefit and screening tool, and it’s free PSA use, while controversial as a screening tool, is increasing. Which brings us to the national guideline standards and review of the current screening recommendations for PSA and prostate cancer. All of the guidelines that we discuss are similar, however I think the NCCN guidelines provide widespread utility, and it is developed by an expert collaborative group that utilizes a multidisciplinary approach of cancer specialists, including surgeons, medical oncologists, and radiation oncologists in developing these guidelines. I wanted to show you this preface in the NCCN guidelines before we actually discussed them. I think it’s very important. The NCCN guidelines recognizes that this disease recognizes a wide spectrum of illnesses, and that while PSA may be helpful, it has the limitations of detecting malignancies versus benign etiologies. That screening might actually not clinical useful in all cases. And it can miss cancers that don’t produce PSA. Screening PS elevations may also lead to unnecessary morbidity and biopsy such as pain, bleeding, and infections. PSA can also discover cancers that aren’t clinically significant and lead to unnecessary treatment. This is the actual guideline. It’s somewhat busy, but it’s not very complicated if you actually look at it. It emphasizes shared decision-making with patients regarding PSA screening, which should include a history in physical, history of cancer in the family, especially prostate cancer. Any known germ line mutation, such as BRCA1 and BRCA2 in the family. Race, a patient’s medication history, as some medications such as finasteride may actually lower the PSA. Based upon these findings, the patient and the physician should have a discussion about how they wish to proceed. Once it is determined that the patient and the physician agree to participate in a PSA screening program, it is strongly recommended that a digital rectal examination be part of that as a baseline. However, DRE as a standalone test has not been found to be particularly helpful in detecting prostate cancer. The guideline is broken down into risk groups based on age, race, and other risk factors. And men age 40 to 75 depending upon race, or those at high risk based upon germ line mutation, the guideline is shown, PSA less than one, repeat every one to four years. Repeat every two to three years if PSA is greater than three or suspicious. DRE repeat if suspicious findings, further evaluation include referral to a urologist. And asymptomatic men with no known risk factors or over 75 PSA is not recommend. If PSA screening has been part of their health maintenance at a younger age, then guidelines could continue at four-year intervals. The US Preventive Task Force recommendation on PSA created quite a bit of controversy, as they did not recommend PSA screening. However, in the population of men that they thought should be considered, it was 15 years later than that of the NCCN and guidelines at 55. A discussion regarding the issue should be done with the patient and physician. This grade was a grade C, indicating there was some controversy, and not a lot of great data to indicate that PSA screenings should be done. In men over 70, it was recommended that it not be performed. You may ask, why is this? Here is 1,000 men that were studied by the USPTF to come up with the recommendations. Of 1,000 men age 55 to 69 that were screened, 240 of them would have positive PSA results. Many of them would have false positive results, elevated PSA but no cancer. Most of these men would get a biopsy with potential side effects of the biopsy. Ultimately less than half of the men with elevated PSA would actually have prostate cancer, 100 of the 1,000. Of the 100 that had prostate cancer, 80 of them would ultimately elect, have treatment, either with surgery or radiation. And of those 80 patients that would be treated, 50 would have, of the 80 would have erectile dysfunction, and 15 of the 80 would have urinary incontinence. The final outcome of those 1,000 screened individuals, 1.3% of 1,000 screened men would avoid a cancer death. Three of 1,000 would avoid cancer metastasis, and five of 1,000 would die of prostate cancer despite screening. So the actual benefit is 1.3 per 1,000. The final guideline that I will discuss is that of the American Cancer Society. It is the least complex, but does discuss the same issues that the other guidelines review. Recommendations for men age 50 who are at average risk and expect to live at least 10 years to have a PSA screening. Men at age 45 or younger who are at high risk beginning PSA screening at that age, and men age 40 who have a first degree relative or have a germ line mutation to start PSA screenings. Men who choose to have screenings should have it every two years initially if the PSA is below 2.5, and annually if it’s over 2.5. Stop screening if life expectancy is less than 10 years. There other guidelines that include the American Urological Association, the American Association of Family Practitioners, and the AUA guidelines, all similar to the NCCN guidelines in its complexity and multi-faceted discussion. The American Academy of Family Physicians does not recommend PSA screenings at all. Patient-centered tools to discuss this with patients are available from the American Cancer Society, ASCO, and the Mayo Clinic, available free for you to use on their websites. In summary, PSA screening guideline conclusions, not one size fits all. There are varying risks associated with prostate cancer, screening based upon age, both personal and family history and race. There are risk of screening, including risk of biopsy, risk of unnecessary treatments and injury, and worry. It is not a perfect test. A normal PSA can still miss cancers, and unfortunately often very aggressive cancers. Hopefully with time, there will be improvements in either this biomarker or other biomarkers for screening of prostate cancer.

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