1 PSA Screening for Prostate CancerRoss Moskowitz, MD Resident Physician Atreya Dash, MD Assistant Clinical Professor

2 Objectives Overview of Prostate Cancer What is screening?What are advantages? What are the disadvantages? What should an individual do? This talk intends to review the basic knowledge a new patient or heathcare provider needs to know in regards to prostate cancer, specifically in regards to prostate cancer screening. This is a controversial topic, with many differing opinions on how screening should be performed, if at all, leaving a confusing terrain for doctors and patients to maneuver.

3 What is Prostate Cancer?The prostate is a gland located in a critical area in the pelvis near the rectum, bladder and urethra Purpose is to liquefy semen Adjacent to the urethral sphincter (urine control valve) and the neurovascular bundles (nerves responsible for erections) The prostate gland is anatomically part of the urinary tract, and plays a functional role in fertility. It is about the size of a walnut, usually weighing between 20 and 50 grams in an adult male, and the urethra courses through it as it exits the bladder. As a gland it excretes fluid to alter the viscosity of semen. As this image depicts, it lies in close proximity to many pelvic organs, and cancer usually grows on the back side of it, adjacent to the rectum. This is known as the peripheral zone, and it is palpable on digital rectal exam.

4 What is Prostate Cancer?Other than skin cancer, prostate cancer is the most common cancer in American men The second leading cause of cancer death in the U.S. Second to only lung cancer as the leading cause of cancer death in American men About 1 man in 36 will die of prostate cancer In terms of overall cancer incidence, prostate cancer is very common, and also is a frequent cause of death from malignancy.

5 What is Prostate Cancer?This image, produced by the American Cancer Society, demonstrates both the incidence of different malignancies, as well of the incidence of estimated cancer deaths based on the data from previous years, separated by sexes.

6 What is Prostate Cancer?About 1 man in 6 will be diagnosed with prostate cancer during his lifetime Nearly two thirds are diagnosed in men aged 65 or older Rare before age 40 Average age of diagnosis is about 67 The American Cancer Society estimates for the U.S. in 2012: 241,740 new cases will be diagnosed 28,170 men will die of prostate cancer Prostate cancer is so common that a significant proportion, 1 in 6, American men will be diagnosed during his lifetime. Although many men will be diagnosed with prostate cancer, a small fraction of those patients will die from this disease.

7 What is Prostate Cancer?This graph, courtesy of the NCHS/CDCP, shows the rates of cancer deaths to a variety of malignancies in men. It is important to note on this chart that prostate cancer is second to only lung and bronchus cancer, and since the early 1990’s the death rate from prostate cancer has been decreasing.

8 What is Prostate Cancer?Most men diagnosed with prostate cancer do not actually die from it More than 2.5 million men in the U.S. who have been diagnosed with prostate cancer at some point are still alive today There are also differences between races in diagnosis and outcomes Many men live with prostate cancer for many years after their diagnosis, and as previously stated, does not always result in death in these patients. Also important to note, there are also differences between races in terms of incidence and outcomes.

9 What is Prostate Cancer?SEER, which is surveillance epidemiology and end results, compiles Medicare data to provide information on cancer statistics to help reduce the burden of these disease on the U.S. population. These graphs have divided by race both the incidence and mortality from prostate cancer. The rise in incidence in the early 1990’s is commonly attributed to the application of the PSA blood test as prostate cancer screening. As seen here African American males have the highest incidence and mortality from prostate cancer, where as Asian/Pacific Islanders, American Indians, and Alaska Natives have the lowest.

10 *Per 100,000, age adjusted to the 2000 US standard population.Cancer Incidence and Death Rates* by Site, Race, and Ethnicity†, US, *Per 100,000, age adjusted to the 2000 US standard population. Prostate Cancer White African American Asian American or Pacific Islander American Indian or Alaska Native Hispanic/ Latino Incidence 142.8 230.8 79.7 101.2 126.7 Mortality 22.4 54.9 10.5 20.7 18.5 Race and ethnicity categories are not mutually exclusive; persons of Hispanic origin may be of any race. Data based on Contract Health Service Delivery Areas, comprising about 55% of the US American Indian/Alaska Native population; for more information, please see: Espey DK, Wu XC, Swan J, et al. Annual report to the nation on the status of cancer, , featuring cancer in American Indians and Alaska Natives. Source: Incidence: NAACCR, Data are collected by cancer registries participating in the National Cancer Institute’s SEER program and the Centers for Disease Control and Prevention’s National Program of Cancer Registries. Mortality: National Center for Health Statistics 2011. American Cancer Society, Surveillance Research, 2012 This table displays the numerical SEER data for the incidence and mortality from prostate cancer. Again note the higher relative incidence and mortality in the White and American American populations relative to Asian/Pacific Islander.

11 What is Screening? Screening is actually a disease prevention strategy called: secondary prevention Primary prevention Prevent a disease before it can ever start Daily aspirin to prevent heart disease Smoking cessation to prevent lung cancer The main goals in public heath policy or recommendations for common diseases is prevention and/or early diagnosis and treatment. Primary prevention is directed at stopping diseases in the public before they can start, such as encouraging smoking cessation, or lifestyle changes like taking a baby aspirin to prevent heart disease. Screening is a form of prevention known as “secondary prevention.”

12 Secondary Prevention Identifying a disease before a patient has symptoms Without symptoms patient unable to complain about a problem that needs evaluation Relies on some sort of test where both disease being tested and test itself meet acceptable criteria Secondary prevention is defined as identifying a disease in a population before a patient has symptoms. Because these patients do not have symptoms, they typically do not present to health care providers with some sort of complaint. And so, this screening process relies on a test where an appropriate disease can be easily identified by a diagnostic exam.

13 Principles of ScreeningThe disease being screened is public health burden There is a phase where the disease is detectable and prevalent Treatment exists for the detected disease Early detection improves outcome with acceptable side effects Screening tests are acceptable to the population, inexpensive and effective There are certain criteria to meet an acceptable screening program. As outlined above: the disease being screened is public health burden, there is a phase where the disease is detectable and prevalent, treatment exists for the detected disease, early detection improves outcome with acceptable side effects, screening tests are acceptable to the population, and are also inexpensive and effective tests.

14 Principles of Screening (PSA)The PSA test and its use for Prostate Cancer meet these criteria PSA is a simple blood test No special requirements such as fasting Measures the level of Prostate Specific Antigen However, not so simple to interpret and explain At its onset of application, the PSA test met these criteria, since prostate cancer is prevalent and poses a significant public health burden, and PSA is an easy and relatively inexpensive blood test; however, it is not perfect it is ability to offer a clear cut algorithm for further diagnosis and treatment.

15 Principles of Screening (PSA)Early detection improves outcome with acceptable side effects Reduces cancer deaths Acceptability of side effects depends on the individual Screening tests are acceptable to the population, inexpensive and effective Effective in reducing cancer deaths Inexpensive Again acceptability to individuals and its application in a population is a problem In addition, prostate cancer screening has the potential to reduce the amount of cancer deaths and a blood test is easily applied and accepted by health care providers and the general population.

16 Issues in favor of prostate cancer screeningThe long period of time before symptoms allows for early detection Cancer causing death is bad, but the spread of disease is also bad due to painful symptoms and need for palliative treatment Screening is convenient and cheap PSA (blood test) DRE (digital rectal exam, palpate for nodules/irregularities) Screening for prostate cancer currently involves the PSA blood test and a digital rectal exam, which are both fairly easy and painless to perform. The digit rectal exam consists of a health care provider inserting a finger into the rectum of a patient and palpating the prostate which can be felt anterior to the rectum. Ideas in favor of prostate cancer screening include the challenge of the long period of time before prostate cancer patients become symptomatic, and when they do become symptomatic they are typically in dire need of palliative treatments. These treatments usually present as bone pain secondary to metastatic disease, or obstruction of the urinary tract.

17 Issues in favor of prostate cancer screeningTreatments for early disease Variety of choices Surgery, radiation, and other ablative treatments One choice is observing the cancer until gets worse Active surveillance Watchful waiting Another advantage to prostate cancer screening is if a patient is diagnosed it allows for an open dialogue between a patient and his urologist in what intervention, if any should be utilized. Based on patient age and comorbidities, and concerns of side effects from treatments, patients can select the most appropriate path of care. Sometimes observation until the cancer gets worse is selected. Active surveillance involves close monitoring of PSA and DRE and repeat prostate biopsies. Watchful waiting is basically waiting until the patient does become symptomatic until an intervention is selected.

18 Issues against prostate cancer screeningHigh prevalence of non-aggressive disease Most patients will not have problems even if their cancer is left alone Inconsistency of disease progression It is unknown how a cancer will behave Arguments against prostate cancer screening are usually based on over diagnosing the disease, and identifying patients with low grade disease who may never require a treatment, as they will not likely ever have symptoms or die from the disease. This knowledge may cause unforeseen stress on a patient. In addition, we unfortunately at this time have a reliable means to predict those patients who will have progression of their prostate cancer.

19 Screening more harmful than beneficial?A large number proportion of the cancers detected will be insignificant Potential for over-diagnosis There are side effects of the treatment but unpredictable if will occur and severity A problem of the test itself A problem of how the test is applied The difficulty of this potential for over diagnosis continues, since if a treatment is selected it is also difficult to predict how severe the side effects may be in any given patient. This makes for a very complex and confusing conversation between doctors and patients.

20 What Does a High PSA Mean and What Next?There is no cutoff level for PSA The risk of finding cancer, and more advanced disease, increases as PSA level increases The PSA is useful in conjunction with a physical exam of the prostate (DRE) If the PSA level and exam warrant, the next step is to perform a prostate biopsy There is no true normal for PSA. Typically the PSA goes up as the prostate grows, which is as a male ages, but also may be elevated in the setting of inflammation (acute or chronic) or a variety of prostatic irritation. Even frequent bike riding has been implicated in the raising of the PSA. The PSA velocity, meaning the rate at which it changes, and the PSA density, comparing the level of PSA to estimated prostate volume may give a practitioner an idea of how concerning a mildly elevated value is, but a DRE and review of risk factors are also included in the discussion if a prostate biopsy is needed.

21 Prostate Biopsy The biopsy is usually an office procedureA minor prep with use oral antibiotics and an enema or other laxative before An ultrasound probe is inserted into the rectum There is a separate channel within the probe to insert the biopsy gun Prostate biopsies are performed by a urologist in the outpatient setting and are generally well tolerated. It takes 15 minutes to perform, and is done via transrectal ultrasound guidance. The prostate is visualized in the sagittal and transverse planes as the needle biopsies are taken.

22 Prostate Biopsy Local anesthetic is injected and the prostate is measured and examined In the U.S. 12 cores are typically obtained Should be only mild discomfort The firing of the gun can be disconcerting Risks Blood in urine, bowel movements, and semen Urinary tract infection Severe infection, requiring hospitalization and intravenous antibiotics Lidocaine is used as the local anesthetic, and usually only a small amount of discomfort is experience by the patient. Prostate volume and dimensions are measured for later interpretation or operative planning.

23 What is the most up to date information?We know treating prostate cancer saves some people from dying from prostate cancer This is from a randomized controlled trial from Sweden where one group of patients had their prostates surgically removed versus a comparison group that was observed Bill-Axelson A, et al.; Radical prostatectomy versus watchful waiting in early prostate cancer. N Engl J Med (18): We are left with a variety of studies to interpret in order to determine on which areas to focus for improved prostate cancer screening and care.

24 What else did the Swedish study tell us?Some people are helped more than others Patients younger than 65 had greater benefit Even patients with less aggressive cancers benefitted Number needed to treat This the number of patients who were operated on to prevent one patient from dying from prostate cancer In the revised estimate from 2011 Overall: 15 men to save one In men younger than 65: 7 to save one The frequent concern is that we are over diagnosing, and so over treating prostate cancer. Often the number needed to treat to prevent a prostate cancer death is extrapolated from collected data, as it was in the Swedish study. Here we learned that we have to treat multiple patients to save one; however in a younger patient population, we need to treat fewer patients to save one.

25 Are there studies about screening?Three recent studies Prostate Lung Colorectal Ovarian Screening Study performed in the U.S. European Randomized Screening Prostate Cancer (ERSPC) Study Göteborg Sweden cohort of ERSPC Each study has a weakness Derive conflicting conclusions The PLCO study, and the ERSPC study and its cohort study offer more conclusions for us to interpret and base clinical decisions on.

26 Are there studies about screening?A summary of these studies Number needed to screen to prevent one prostate cancer death: As many as 1410 men to as low as 293 men Number needed to treat for prostate cancer to prevent one death (from a group of patients identified by screening): As many as 48 men to as low as 12 men Ultimately these studies concluded that a large amount of patients ( ) need to be screened to save one life from prostate cancer, and similarly, men need to be treated for prostate cancer to save one life.

27 What are the side effects?Small risks with biopsy Side effects are mainly associated with treatment The likelihood and severity of the side effects depend on the treatment selected and patient characteristics, but are not readily predictable The issue is that these side effects can have a detrimental effect on quality of life Biopsy itself does carry small risks of infection, which rarely requires hospitalization, and bleeding; however it is the treatments themselves that tend to be the most morbid and carry the weight of the problem of over diagnosis. The side effects vary in terms of frequency and severity, and usually relate to urinary continence and potency, but do not stop there in the impact on overall quality of life.

28 What are the side effects?Treatments Surgical removal Radiation Administered from an outside energy source focused on the prostate Radioactive seed implants Hormonal blockade No typically given as primary treatment Newer ablative treatments Observation Least organic side effects in the absence of disease progression Side effects Urinary Incontinence Bother related to obstruction or irritation Sexual Loss of erections Loss of libido Bowel Irritation Risk of fistula Vitality Related to use of hormonal therapy There are a variety of treatments a urologist can review with a prostate cancer patient, and paying particular attention to the efficacy and side effects of each. The patients values and concern of side effects need to play the central role in deciding a treatment plan.

29 What are the side effects?Hormonal Blockage (androgen deprivation therapy) Medications: Leuprolide (Leupron): This is typically given as an IM depot shot, it is a LH-RH (lutenizing hormone releasing hormone) analog which stops the cascade that leads to testosterone production, which in turn feeds prostate cancer Anti-androgens: block the body’s use of androgens Flutamide, biclutamide, nilutamide Bilateral orchietomy (removal of the testicles) may also be performed as a surgical form of androgen deprivation therapy Bilateral orchiectomy was discovered as an early treatment to starve prostate cancer of the testosterone it needs to flourish. Now hormone analogs can accomplish the same goals; however some prostate cancer over time does progress to be come hormone refractory, and so these treatments become less effective.

30 What are the side effects?Hormonal Blockage (androgen deprivation therapy) Typical Side effects Decrease in libido, erections, and energy Hot flashes Decrease in testicle size Pain (bone/muscle/joints), flu like symptoms These side effects are hard to predict, but usually are more pronounced in the elderly, and so these medications are often poorly tolerated Again, a review in goals of care, and patient concerns over side effects need to be completed before treatment plan is initiated. A trial of these medications can be carried out and adjusted by an experience urologic oncologist.

31 Should I get screened? (Practical)Am I at risk for cancer including a lethal cancer What is my race? Do I have first degree relatives with prostate cancer? How is my overall health? How old am I? What are my other health problems? What is my risk of cardiovascular disease? There are a variety of questions that need to be asked before initiating a screening or treatment plan for a patient, based around the patients risk for having prostate cancer, or an other more morbid conditions that a patient may die from instead of prostate cancer.

32 Should I get screened? (Experts)American Society of Clinical Oncology (ASCO) In men with a life expectancy <10years, it is recommended that general screening for prostate cancer with total PSA be discouraged, because harms seem to outweigh potential benefits U.S. Preventive Services Task Force (May 22, 2012) The USPSTF recommends against PSA-based screening for prostate cancer (grade D) Clinicians are encouraged to not screen patients unless the individual understands the potential benefits and harms Often we refer to expert medical or public health groups for opinions on the value of prostate cancer screening programs; however recently the USPSTF changed their stance on the value of screening for prostate cancer has left much controversy and confusion of what the right choice truly is.

33 Should I get screened? (Experts)American Urologic Association PSA the only widely available test for prostate cancer when interpreted appropriately, it provides important information in the diagnosis, pre-treatment staging or risk assessment and monitoring of prostate cancer patients. American Cancer Society Informed decision making process Age at which to start and some details vary But even “Expert Panels” have their biases Although the USPSTF does not recommend prostate cancer screening, other organizations, such as the AUA view the PSA as the only test we have, and although it is not perfect, it can be used judiciously in appropriate situations.

34 Problem based learning (PBL) CasesHere we will present two complex and advanced prostate cancer cases that illustrate the issues that arise in geriatric patients with metastatic prostate cancer

35 PBL Cases 78 year old male with history of prostate cancerThis was diagnosed two years ago at the time of transurethral resection of prostate (TURP) surgery (procedure to open prostatic urethra for improved ability to void) Gleason score (grade of severity) was 4+3=7 (6 least severe, 10 most severe) No further intervention (watchful waiting) and PSA followed and was found to be 36.9 (very elevated)

36 PBL Cases Past Medical History: Current Issues:Hypertension, CVA/TIA, seizure disorder, arrhythmia, arthritis, hyperlipidemia, GERD Current Issues: Possible metastatic disease to thoracic spine Elevation in creatinine (worsening kidney function) Renal ultrasound showed left hydronephrosis (blocked urine outflow from left kidney)

37 PBL Cases Interventions: Prostate cancer  Leuprolide injectionsThen elected to have bilateral orchiectomy to stop testosterone production altogether Decreased kidney function Operating room for endoscopic resection to open left ureteral orifice and placement of stent to allow left kidney to drain efficiently

38 PBL Cases 92 year old male found to have PSA of 88Biopsy performed (Gleason 5+5=10, most severe) Thought to initially to have a diagnosis of rectal cancer, but confirmed to be locally advanced prostate cancer Patient with history of urinary retention and obstructed voiding symptoms, received a vaporization procedure of prostate 2 years ago (no tissue for diagnosis obtained)

39 PBL Cases Past Medical History: Current Issues:Coronary artery disease (history of myocardial infarction), atrial fibrillation, melanoma, chronic kidney disease Current Issues: Locally advance prostate cancer causing urethral and ureteral obstruction Leading to worsening lower urinary tract symptoms (incontinence) and worsening renal function

40 PBL Cases Interventions:Prostate cancer  Radiation therapy, then hormonal therapy (leuprolide) Decreased kidney function/ureteral obstruction Managed with bilateral nephrostomy tubes (percutaneous flank tubes that drain urine, require changes by interventional radiologist every few months) Has led to multiple hospital admissions for urinary tract infections and worsening renal function

41 PBL Cases Discussion: Should these patients have had more aggressive initial treatment? Yes: May have avoided or delayed local advancement or metastatic disease No: Poor surgical candidate, and possibly avoid quality of life decreasing interventions Should these patients have been screened? Yes: May have be diagnosed sooner, received treatment sooner, and have not required these morbid interventions No: Advanced age with multiple comorbidities, questionable life expectancy >10yrs and still uncertain if they will die from prostate cancer

42 Thank You