PCRI Patient & Physician in Co-Partnership nsights New Developments in Prostate Cancer Treatment NOVEMBER 2010 VOL 13: NO 4 2010 PROSTATE CANCER CONFERENCE Summary By: Jim O’Hara – PCRI Educational Facilitator PCRI wishes to say a “BIG THANK YOU” to all of the attendees (over 750 from 38 states and 8 countries), speakers, supporters, volunteers, production crew and the Marriott LAX for making the 2010 Prostate Cancer Conference a tremendous success. Many long-time attendees commented it was the “BEST EVER”. CONTENTS 2 From the Editor 3 Understanding and Applying Risk Assessment for Prostate Cancer By Matthew R. Cooperberg, MD, MPH The clues to your personal prostate cancer risk are hidden in your Medical Record. Dr. Cooperberg is one of the most published authors on prostate cancer and has been a leader in the development of the CAPRA prostate cancer risk scoring system developed at U.C. San Francisco. 8 MRI for Prostate Cancer: Information for Patients and Families By Daniel Margolis, MD. Latest MRI technology provides the highest resolution images of cancer in and around the prostate. 14 Targeted Biopsies and Active Surveillance By David Agus, MD. Is it safe to avoid the side-effects of prostate cancer therapy? Risk assessment helps identify who is a candidate for active surveillance. 18 TIP: Testosterone Inactivating Pharmaceuticals By Mark Scholz, MD. On Saturday, the conference was moderated by Dr. Mark Moyad. We had the usual lineup of excellent speakers, who presented cuttingedge information dealing with all stages of (Continued on page 24) prostate cancer. 24 Best of The 2010 Prostate Cancer Conference By Jim O’Hara Highlights from the presentations. 30 PCRI Presents Harry Pinchot and Catalyst Awards EDITOR’S LETTER From The Editor The PCRI believes most men should be screened for prostate cancer. But, if PC is found, many men at low risk might safely delay treatment; possibly for life. This Insights issue reports on a better risk assessment tool, better MRI imaging, and millimeter accuracy targeted biopsies that give men and their doctors better information to use when deciding on therapy options. Why Is The Roosevelt Hotel Painted Blue? Blue September – Changing the face of Prostate Cancer in America W hen you think of the color blue, prostate cancer probably isn’t the first thing that springs to mind. But this year The Prostate Cancer Research Institute (PCRI) teamed together with Blue September, a prostate cancer awareness and fund-raising campaign, to help make that change, and begin to level the playing field to give prostate cancer the profile it deserves. There is no doubt that when it comes to breast cancer, the pink initiative has been a huge success. Not as well known, is that every year in America, more men are diagnosed with prostate cancer than women with breast cancer. But prostate cancer gets nowhere near the same fanfare and public sympathy. — That is, until now! In 2010, the inaugural year of the campaign, the PCRI and Blue September have made huge inroads, getting the word out about prostate cancer and the need for men to be more aware of the disease and get a checkup, by spreading the spirit of blue all over town. Buildings, landmarks, familiar brands and icons, and most importantly, faces, were turned blue, encouraging everyone to �face up’ and get proactive about prostate cancer. (Continued on page 29) 2 PCRI Insights • www.PCRI.org PCRI nsights Editor : Nathan Roundy Review Board: Duke K. Bahn, MD Stanley A. Brosman, MD Arthur N. Lurvey, MD Mark C. Scholz, MD Michael Steinberg, MD Graphic Designer John I. Blanda Prostate Cancer Research Institute 5777 W. Century Boulevard, Suite 800 Los Angeles, CA 90045 Phone (310) 743-2116 | Fax (310) 743-2113 Helpline (310) 743-2110 | E-mail: [email protected] www.pcri.org and www.prostate-cancer.org Board of Directors Chester A. Swenson, President Chairman, Marketing & Financial Services Enterprises Jerome Seliger, PhD, Vice President Professor of Health Administration, California State University, Northridge Barry L. Friedman, JD, Secretary Attorney at Law T. Kent Graham, Treasurer Financial Consultant, T. Kent Graham & Associates Duke K. Bahn, MD Director, Prostate Institute of America Stanley A. Brosman, MD Pacific Urology Institute, Pacific Clinical Research Arthur N. Lurvey, MD Medicare Contractor Medical Director Jerry Peters MCG Records Claudia B. Sangster, Esq. Director of Philanthropy, Estate & Trust Services, Harris myCFO, Inc. Mark C. Scholz, MD, PCRI Co-founder Director, Prostate Oncology Specialists Michael Steinberg, M.D., FAC Professor and Chair, Department of Radiation Oncology, David Geffen School of Medicine at UCLA The cost of printing and mailing this newsletter is made possible through a generous grant from The Life Extension Foundation P.O. Box 229120, Hollywood, FL 33022 800-544-4440 www.lef.org/prostate © 2010 Prostate Cancer Research Institute. All Rights Reserved PCRI Insights, November 2010, Vol 13: No 4 Understanding and Applying Risk Assessment for Prostate Cancer Matthew R. Cooperberg, MD, MPH Introduction: The Heterogeneity of Prostate Cancer W ith over 200,000 new diagnosis every year, prostate cancer is by a wide measure the most common cancer among men in the United States. Over 30,000 men will die of the disease this year.1 This number is surpassed only by lung cancer among cancers affecting men in this country, yet is clearly dwarfed by the number of diagnoses. These numbers summarize the challenge of prostate cancer: screening programs based on measurement of prostate specific antigen (PSA) levels among otherwise healthy men are intended to identify and offer early curative treatment to the men at risk of dying of prostate caner — and indeed, since PSA screening started in earnest in the early 1990s, prostate cancer mortality rates at the population level have fallen about 40%.1 But in the course of identifying the potentially lethal prostate cancers, many more tumors are found that are indolent, i.e., that would never cause symptoms or reduced lifespan if they were never detected. Most men with prostate cancer in fact die of heart disease — just like men who have not been diagnosed with prostate cancer. The side effects and costs of over-treating these low-risk prostate tumors amount to one of the most substantial public health problems related to the disease. The obvious solution is to treat only those prostate cancers that are likely to cause problems and ignore the rest. In fact, the last several years have seen significant progress toward this paradigm of selective and risk-adapted treatment. Men with low-risk prostate cancer — tumors unlikely to progress — are now offered active surveillance: careful monitoring of the tumor with serial PSA tests and repeat prostate biopsies. With large cohorts of hundreds of men now reported from major centers across North America, this strategy is increasingly accepted as safe and effective: for the large majority of men with low-risk tumors, the window of opportunity for cure lasts for years, so treatment after a period of surveillance (e.g., if the PSA is rising consistently) is as likely to cure as immediate treatment. In the interim, the risks and side effects of surgery, radiation therapy, hormonal therapy, etc. may be avoided.2 Men with intermediate-risk cancer generally should receive surgery or radiation therapy, and those with higher-risk prostate cancer often need combination therapy — either surgery followed by radiation or radiation together with hormonal therapy. (Continued on page 4) “Since the early 1990s, prostate cancer mortality rates at the population level have fallen about 40%” “For men with low-risk tumors ... treatment after a period of surveillance is as likely to cure as immediate treatment” www.PCRI.org • PCRI Insights 3 UNDERSTANDING AND APPLYING RISK ASSESSMENT FOR PROSTATE CANCER The Key Players: PSA, Gleason Grade, and Tumor Extent Risk-stratifying prostate cancer — determining which are at low-, intermediate-, or high-risk—is thus absolutely critical to effective treatment. How exactly to use risk stratification in practice is at once simple and complex. The simple part is what factors to consider, as there is broad agreement on the key determinants of prostate cancer risk. First is the blood level of PSA. For all the controversy surrounding PSA testing for prostate cancer screening, the test is quite reliable in predicting outcomes among men who have already been diagnosed with cancer. Except in rare cases, the lower the PSA, the lower the cancer risk. PSA levels under 10 are usually considered low-risk, but even within the <10 category, lower is better. When the PSA is over 20 at time of diagnosis, there may be detectable cancer outside the prostate, so imaging tests such as bone scans are ordered to rule out metastatic disease. The second key risk factor is the Gleason grade, which is a measure of the aggressiveness of the cancer cells as determined by the pathologist examining prostate tissue (e.g., from a biopsy) under the microscope. The Gleason grade is assigned on a 1 to 5 scale, but in contemporary practice grades 1 and 2 are rarely seen, so for practical purposes, Gleason grade 3 indicates low-grade cancer, Gleason 4 indicates intermediate-grade, and Gleason 5 indicates highgrade. Prostate cancer can be heterogeneous even within an individual prostate, so the Gleason score is expressed as two numbers: the first number is the primary pattern—i.e, the most common pattern—and the second number is the secondary pattern. The two numbers are sometimes added for a final score, but are better expressed as a primary + secondary score. A Gleason 3+3 (or Gleason 6) tumor, for example, is uniformly low-grade. A Gleason 3+4 tumor is mostly low grade with some intermediategrade, whereas a Gleason 5+4 tumor is mostly highgrade with some intermediate-grade. In terms of grade, the major driver of prostate cancer risk is the primary pattern. Thus Gleason 4+3 tumors are significantly more aggressive than Gleason 3+4 tumors—which is why lumping all such cases as “Gleason 7” is not ideal. The PSA and Gleason score are the most important risk parameters in most cases. The third is some 4 PCRI Insights • www.PCRI.org FROM PAGE 3 measure of tumor extent—how much cancer there is and where it is. There are different ways to articulate extent. The most common is tumor clinical stage, and is expressed with three letters: T, N, and M. A tumor which is not palpable on rectal exam or visible on imaging tests (e.g., ultrasound) is designated T1, one which is palpable or visible but is confined to the prostate is T2 (with subtypes T2a, 2b, and 2c depending on how large the palpable tumor is), and one which is felt or seen to extend beyond the edge of the prostate is T3. If there are involved lymph nodes, the cancer is N1, and if there are metastases in the bones or elsewhere, it is M1. Metastatic (i.e., N1 or M1) cancer is very uncommon at diagnosis in the era of PSA screening, and the large majority of tumors are stage T1 or T2. The problem is that neither rectal exams nor imaging tests are particularly accurate in identifying tumors which are confined to the prostate, and as a result clinical stage offers little information when considered in context of other variables such as PSA and Gleason grade for tumors which are confined to the prostate.3 A more accurate measure of tumor extent is to quantify how much cancer is seen on biopsy. This can be measured as the number or percent of biopsy cores positive—for example, if a 12-core prostate biopsy is performed and 10 cores are involved with cancer, the volume of cancer is greater than if only 2 cores are involved. Some pathologists will also report the extent of cancer involvement within each needle core. Putting It All Together Once the PSA, Gleason score, and tumor extent is determined, the question becomes how to integrate this information to give an overall sense of cancer risk. This question is more complicated than identifying the variables: by one count there are over 100 formulae, calculators, nomograms, and other instruments intended to determine risk at various prostate cancer decision points.4 Most are based on PSA, Gleason, and clinical stage and/or some measure of biopsy core involvement; some add other parameters such as patient age, year of diagnosis, or prostate size (which can impact interpretation of the PSA). One of the first widely-adopted approaches to risk stratification is a 3-level risk group classification published by Anthony D’Amico and colleagues at UNDERSTANDING AND APPLYING RISK ASSESSMENT FOR PROSTATE CANCER Harvard University5 and formally adopted by the American Urological Association’s practice guideline for localized prostate cancer treatment.6 In this classification, men are assigned to one of three groups as follows: FROM PAGE 4 Figure 1: Kattan Nomogram Low-risk: PSA ≤10, Gleason ≤6, and clinical stage T1 or T2a Intermediate-risk: PSA 10-20, Gleason 7, or clinical stage T2b High-risk: PSA >20, Gleason 8-10, or clinical stage T2c or T3a The major advantage to this system is its simplicity, and it is used very commonly. However, it has significant drawbacks. First, it over-weights T stage which, as noted above, is not a very accurate measure of tumor extent within the T2 category. Second, it does not distinguish between Gleason 3+4 and 4+3 tumors which (again, as noted above) behave very differently within the Gleason 7 category. Finally, and most importantly, it does not combine information from the risk variables. A PSA 18, Gleason 4+3, stage T2b tumor and a PSA 4, Gleason 3+4, stage T1c tumor are both “intermediate-risk” in this classification, but would be expected to behave quite differently. Multivariable models combine PSA, Gleason grade, and other parameters, integrating information from each to give a more accurate overall impression of risk. There are many such models, and though the math underlying them tends to be similar, there are several different ways to present the data. For example, Alan Partin and colleagues at Johns Hopkins University published a set of lookup tables to predict outcomes after surgery such as extra-prostatic extension of tumor.7 The tables simply list likelihoods for the outcome of interest for men with a given set of risk factors (again, PSA, Gleason score, and T stage), and are used as a reference. Nomograms are another popular way of presenting information from multivariable risk models. Popularized by Michael Kattan and Andrew Stephenson and colleagues at Memorial-Sloan Kettering and the Cleveland Clinic, nomograms are graphs on which a patient is assigned a set number of points for each variable of interest; the points are then summed to predict the outcome of interest, which is given with a ±10% margin of error. For example, using the original nomogram published by Kattan,8 which predicts likelihood of remaining free of recurrence 5 years after surgery, the patient mentioned above with PSA 4, Gleason 3+4, stage T1c disease would receive 84 points (37 + 47 + 0) corresponding to a roughly 84% ±10% likelihood of recurrence-free survival. The patient with PSA 19, Gleason 4+3, stage T2b would receive 155 points (74+50+31), indicating a 25% ±10% likelihood of recurrence-free survival. An updated version incorporates data on the number of biopsy cores involved with cancer.9 Many other nomograms have been published since, intended to predict pathologic outcomes (similar to the Partin tables), biochemical outcomes after surgery or radiation therapy, or longer-term outcomes like metastasis or mortality.4 Two important caveats should be noted. First, a given nomogram is developed based on data from a specific cohort of men, usually treated in one or a few academic centers in which a small number of highly-trained surgeons or radiation oncologists treat large volumes of patients. A great deal of caution must be exercised in calculating specific risks of recurrence for patients treated in other settings by different clinicians, and ideally nomograms should be formally validated in a given setting before they are used routinely in that setting. Second, with computer software it is very easy to calculate multiple nomogram scores simultaneously, creating a temptation to use the nomogram scores to compare treatment options such as surgery or radiation. Nomograms cannot be used this way—the cohorts of patients used to develop each are very different, as are the definitions of the outcomes reported. In particular, with few exceptions nomograms predict likelihood of PSA recurrence after treatment, (Continued on page 6) www.PCRI.org • PCRI Insights 5 UNDERSTANDING AND APPLYING RISK ASSESSMENT FOR PROSTATE CANCER FROM PAGE 5 cohorts—our group at the University of California, San Francisco developed the UCSF Cancer of the Prostate Risk Assessment (CAPRA) score, which is intended to combine the accuracy of nomograms with the ease of calculation of the a risk grouping system.10 To calculate the CAPRA score, points are assigned based primarily on the PSA and Gleason score, with lesser weights given to T-stage, percent of biopsy cores positive, and patient age: Figure 2: CAPRA Score Matthew R. Cooperberg, MD, MPH Matthew R. Cooperberg earned MD and MPH degrees concurrently from Yale University in 2000. He completed his General Surgery and Urology training, and a fellowship in Urologic Oncology, at the University of California San Francisco, where he subsequently joined the faculty. He has written over 70 peer-reviewed scientific articles. He lives in San Francisco with his wife and son. which is defined very differently after radiation than after surgery. Thus nomograms may be useful to give a patient undergoing a specific treatment a sense of the likely outcomes, but cannot help guide treatment decisions. The CAPRA Score Because of these limitations—and the fact that nomograms are difficult to calculate for hundreds or thousands of patients in research settings and cannot be used to consistently identify low- or high-risk 6 PCRI Insights • www.PCRI.org Points are added to yield a 0-10 score. Overall, every 2-point increase in score (e.g., from 2 to 4 or from 5 to 7) indicates roughly a doubling of risk. CAPRA scores in the 0-2 range indicate relatively lowrisk disease, CAPRA 3-5 tumors are intermediate-risk and CAPRA 6-10 tumors are high-risk. Assuming they were over 50, with clinical stage T1 or T2 and <33% of biopsy cores positive, the two hypothetical patients described above would have CAPRA scores of 2 and 6, placing them in the low- and high-risk groups, respectively. The CAPRA score was developed based on data from men in the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) registry, which includes men treated at dozens of clinical sites, mostly community-based, across the U.S.. It has also been validated in a large academic center cohort,11 and in multi-center cohorts of men in the Veterans Affairs system12 and in Europe.13 It was recently found to offer better accuracy than competing instruments in an independent head-to-head comparison based on another European cohort.14 Moreover, it has been shown to predict metastasis and mortality as well as biochemical outcomes—after surgery, radiation therapy, and hormonal therapy.15 UNDERSTANDING AND APPLYING RISK ASSESSMENT FOR PROSTATE CANCERR The CAPRA score can be determined without a complex table or software, and with a little practice can be calculated from memory. Moreover, it is easy to calculate for many patients at once and has been validated in multiple settings using the same definitions of low, intermediate-, and high-risk, so is ideally suited for the research setting as well as for clinical practice. It is important to note that the CAPRA score is primarily meant to indicate relative rather than absolute risk. Thus a tumor with a CAPRA score of 4 has an intermediate-risk of recurrence or progression after surgery or radiation. This tumor will be more likely to progress than one with a score of 2, and less likely than one with a score of 6, regardless of treatment approach or setting. The specific risk (e.g., likelihood of being free of disease at 5 years after treatment), while roughly consistent across different cohorts, will depend at least in part on factors such as surgeon skill and experience, pathology grading practices, etc. Conclusion: Risk Assessment In Practice Data from the best available studies reported to date leave little question that prostate cancer screening saves lives.16 However, there is also no question than many men are harmed by over-treatment resulting in such screening efforts. High-quality treatment for prostate cancer entails some determination of overall risk, using the D’Amico classification at a minimum, but preferably using a multivariable tool such as a nomogram or the CAPRA score. Treatment in turn should be guided by cancer risk and an individual man’s overall health and life expectancy (not necessarily by his chronological age). Though some trends are slowly improving, there is still too much variation in prostate cancer care, too much over-treatment of low-risk disease, and frequent under-treatment of high-risk disease.17 It is important to remember that even high-risk prostate cancer is slow to progress compared to lung, pancreas, and other aggressive malignancies. So there is almost always ample time to seek multiple treatment options and to make a carefully considered decision. Lower risk prostate cancers grow so slowly that some thought leaders are starting question whether they should even be called “cancer” at all,18 given the substantial psychological impact of the word itself. Consistent use of risk stratification tools will ameliorate both over-and under-treatment, will save millions of dollars in needless health care expenditures, and ultimately will improve both survival and quality of life for the hundreds of thousands of men diagnosed each year in the U.S. and worldwide. REFERENCES 1. Jemal A, Siegel R, Xu J, Ward E. Cancer Statistics, 2010. CA Cancer J Clin. 2010. 2. Dall’Era MA, Cooperberg MR, Chan JM, et al. Active surveillance for early-stage prostate cancer: review of the current literature. Cancer. 2008;112(8):1650-1659. 3. Reese AC, Cooperberg MR, Carroll PR. Minimal impact of clinical stage on prostate cancer prognosis among contemporary patients with clinically localized disease. J Urol. 2010;184(1):114-119. 4. hariat SF, Karakiewicz PI, Roehrborn CG, Kattan MW. An updated catalog of prostate cancer predictive tools. Cancer. 2008;113(11):30753099. 5. D’Amico AV, Whittington R, Malkowicz SB, et al. Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. JAMA. 1998;280(11):969-974. 6. Thompson I, Thrasher JB, Aus G, et al. Guideline for the management of clinically localized prostate cancer: 2007 update. J Urol. 2007;177(6):2106-2131. FROM PAGE 6 7. Partin AW, Kattan MW, Subong EN, et al. Combination of prostate-specific antigen, clinical stage, and Gleason score to predict pathological stage of localized prostate cancer. A multi-institutional update. JAMA. 1997;277(18):1445-1451. 8. Kattan MW, Eastham JA, Stapleton AM, Wheeler TM, Scardino PT. A preoperative nomogram for disease recurrence following radical prostatectomy for prostate cancer. J Natl Cancer Inst. 1998;90(10):766-771. 9. Stephenson AJ, Scardino PT, Eastham JA, et al. Preoperative nomogram predicting the 10year probability of prostate cancer recurrence after radical prostatectomy. J Natl Cancer Inst. 2006;98(10):715-717. 10. Cooperberg MR, Pasta DJ, Elkin EP, et al. The University of California, San Francisco Cancer of the Prostate Risk Assessment score: a straightforward and reliable preoperative predictor of disease recurrence after radical prostatectomy. J Urol. 2005;173(6):1938-1942. 11. Zhao KH, Hernandez DJ, Han M, Humphreys EB, Mangold LA, Partin AW. External validation of University of California, San Francisco, Cancer of the Prostate Risk Assessment score. Urology. 2008;72(2):396-400. 12. Cooperberg MR, Freedland SJ, Pasta DJ, et al. Multiinstitutional validation of the UCSF cancer of the prostate risk assessment for prediction of recurrence after radical prostatectomy. Cancer. 2006;107(10):2384-2391. 13. May M, Knoll N, Siegsmund M, et al. Validity of the CAPRA score to predict biochemical recurrencefree survival after radical prostatectomy. Results from a European multicenter survey of 1,296 patients. J Urol. 2007;178(5):1957-1962. 14. Lughezzani G, Budaus L, Isbarn H, et al. Head-to-head comparison of the three most commonly used preoperative models for prediction of biochemical recurrence after radical prostatectomy. Eur Urol. 2010;57:562-568. 15. Cooperberg MR, Broering JM, Carroll PR. Risk assessment for prostate cancer metastasis and mortality at the time of diagnosis. J Natl Cancer Inst. 2009;101(12):878-887. 16. Schroder FH, Hugosson J, Roobol MJ, et al. Screening and prostate-cancer mortality in a randomized European study. N Engl J Med. 2009;360(13):1320-1328. 17. Cooperberg MR, Broering JM, Carroll PR. Time trends and local variation in primary treatment of localized prostate cancer. J Clin Oncol. 2010;28(7):1117-1123. 18. Esserman L, Shieh Y, Thompson I. Rethinking screening for breast cancer and prostate cancer. JAMA. 2009;302(15):1685-1692. Back Issues of PCRI Insights are Available at www.PCRI.org www.PCRI.org • PCRI Insights 7 MRI PCRI Insights, November 2010, Vol 13: No 4 Prostate MRI: Information for Patients and Families Daniel J A Margolis, MD Co-Director, Prostate MRI Adjunct Clinical Professor of Radiology David Geffen School of Medicine at UCLA P rostate cancer affects nearly all of our lives, but it affects different people in different ways. Sometimes an abnormal blood screening test (for PSA, prostate specific antigen) will suggest cancer, but none is found at biopsy. Sometimes a decision has to be made whether to treat what appears to be a very small amount of cancer and risk the associated side effects. Sometimes a patient who is thought to be a good surgical candidate will turn out to have cancer that cannot No other imaging technique is as good as MRI for delineating the prostate and surrounding tissues and detecting cancer within the prostate be treated surgically. One new consideration is, with stereotactic radiosurgery and robotic-assisted laparoscopic surgery, can we formulate a more accurate treatment plan ahead of time? All of these are issues where prostate MRI (magnetic resonance imaging) can potentially provide value. 8 PCRI Insights • www.PCRI.org We all know that prostate cancer is the most common (non-skin) cancer and second leading cause of cancer death in American men, but it has relatively low mortality (death rates) compared with many other cancers such as lung, breast, and colon(1). In other words, most men die with prostate cancer, but not from it. The challenge, then, is to try to find all prostate cancer but treat only that cancer which is aggressive. Currently, the standard of care is to screen men with a blood test and physical examination (digital rectal examination) and perform “sextant” biopsies, or two biopsies each on the right and left side of the prostate at The challenge is to try to find all prostate cancer but treat only that cancer which is aggressive each of the three levels (apex, midgland, and base). The difficulty is that aggressive prostate cancer may only be found in a small proportion of the prostate, such that biopsies, which sample only a very small proportion of the prostate, may find only non-aggressive cancer or none at all. Because we do not want to let anyone die of prostate cancer, even a small amount of aggressive cancer is considered a reason to consider treatment. PROSTATE MRI: INFORMATION FOR PATIENTS AND FAMILIES FROM PAGE 8 Prostate MRI is not designed to replace the current practices (at least not yet). However, it can be helpful for physicians in specific situations. Some uses been well studied at academic medical centers and have become part of the work-up of prostate cancer at these centers. Other indications are rather new and relatively unproven, with few supportive studies in the medical literature, but many show promise and may enter the standard clinical arena soon. There are 4 ways that prostate MRI has been shown useful in the work-up of prostate cancer 1. Surgical Planning 2. Suspicious PSA, Negative Biopsies 3. Radiation Therapy Planning 4. Abnormal PSA After Surgery or Radiation Therapy, “Biochemical Failure” Surgical Planning Although most surgeons neither use nor really need MRI for surgical planning, there are certain cases where it is useful. For the most part, a surgeon’s ability to palpate, or feel, the location of cancer tells him or her where to cut. Most surgeons will try to cut out all of the cancer but, if at all possible, spare the nerves next to the prostate which are important for continence and erectile function. The prostate tissue will be examined by a pathologist, and this report will help the surgeon decide if radiation therapy is needed after surgery. In some cases, it can be determined prior to surgery from the PSA level and biopsies that there is an intermediate chance that the patient would need radiation therapy regardless. In these cases, it might make sense to proceed directly to radiation therapy and spare the additional risks of surgery. MRI can be used to determine if all of the cancer is confined within the prostate, which is necessary to prevent the need for radiation therapy(2). With advent of interest in robot-assisted laparoscopic prostate surgery, or “robotic surgery,” surgeons have an immense improvement in control over the surgical field, and are able to see and cut with much finer detail. The only drawback is the loss of palpation, such that surgeons cannot “feel” where the cancer lies. Many will simply cut as close to the nerves as is safe. However, some surgeons are using MRI as a road map, Dr. Daniel Margolis Adjunct Clinical Professor of Radiology David Geffen School of Medicine at UCLA, Los Angeles CA Dr. Margolis received his MD from USC, Los Angeles in 1998 and did his diagnostic radiology residency at UCLA. He was Associate Clinical Professor of Radiology at Stanford University, Stanford CA in 2005-6. He then joined UCLA where he is Co-Director, Prostate MRI, and Adjunct Clinical Professor of Radiology - David Geffen School of Medicine. in lieu of palpation, to determine how to plan their surgeries. This way, they can decide to cut closer to the prostate when it is safe which improves the chances of preserving nerve function, or to give the prostate a wide berth, in those cases where the cancer extends to the edge of the prostate or even slightly beyond. Surgeons can even vary the surgical technique between right and left if one side is safer than the other(3). Suspicious PSA But Negative Biopsies One of the most frustrating and anguishing situations for patients and physicians alike is when the PSA blood test is suspicious, because it is high or rising rapidly, but the biopsies are negative. In this case, the concern is that the biopsies missed the cancer. However, in some cases, the blood test is abnormal because of a benign condition, (Continued on page 10) www.PCRI.org • PCRI Insights 9 PROSTATE MRI: INFORMATION FOR PATIENTS AND FAMILIES such as BPH (benign prostatic hyperplasia) or inflammation referred to as prostatitis. Because it is so important to determine whether or not a patient has aggressive (or any) cancer, some patients would undergo up to three or four repeat biopsies. MRI can find a suspicious area in the prostate in many if not most cases for targeting(4). Some centers can even biopsy a suspicious area during an MRI scan, although this is usually scheduled as a second scan because the hardware is different. Radiation Therapy Planning External-beam radiation planning is usually done with a CT scan. Some centers, which use stereotactic body radiation therapy (SBRT) that combines image-guided and intensity-modulated (IGRT and IMRT) techniques, use a CT scan to plan where to irradiate after metallic beads, “fiducial markers,” have been placed. However, the prostate appears as a gray blob on CT scan. MRI can delineate the prostate in exquisite detail, which is useful in guiding the radiation beams to treat just the cancer and spare the adjacent structures such as the rectum, bladder, and nerves. MRI can also be used to identify suspicious bone lesions and enlarged lymph nodes which could also be treated(5). Conventional brachytherapy, a technique in which radioactive seeds are placed in the prostate, is a well-established treatment for early stage prostate cancer. High-dose brachytherapy instead uses rods, called catheters, which are inserted into the prostate through which highly radioactive seeds are temporarily placed into the prostate and then removed. It has the advantage 10 PCRI Insights • www.PCRI.org FROM PAGE 9 that specific areas in the prostate can be targeted. This has a very low incidence of side effects but is only effective for cancer confined to the prostate. MRI can be used to help determine which are the most suspicious areas in the prostate that need a “boost” of radiation, and to confirm that the prostate cancer is all confined to the prostate. “Biochemical Failure,” Abnormal PSA After Therapy Successful treatment of prostate cancer should result in a “negative” or undetectable blood level of PSA. In some cases, the PSA begins to rise again. This suggests that some prostate cancer may be left. Treatment choices at this point are limited, and it becomes important to determine where the cancer might be. MRI is sensitive for prostate cancer which may have survived radiation therapy, both in the prostate and in the pelvic lymph nodes and bones, and can sometimes find recurrence in the pelvis after the prostate is surgically removed. Other types of scanning (CT, PET, ultrasound) are less sensitive. There are also 3 methods which are being actively investigated but are not widely available. 1. Active Surveillance 2. Biopsy Planning 3. Focal Therapy Planning Active Surveillance One choice for men who only have a very small amount of nonaggressive prostate cancer is active surveillance, previously called “watchful waiting.” Rather than treating the prostate cancer right away, these patients return at regular intervals for a repeat physical examination, blood test, and (usually at longer intervals) repeat biopsy. Despite some confusing and alarming suggestions that biopsies can actually make cancer worse, this has never been proven. However, biopsies are uncomfortable and have the common risks involved with any invasive procedure, and the inflammation from repeat biopsies can make eventual surgery difficult. MRI has two advantages for active surveillance. First, it can identify areas in the prostate that are suspicious for aggressive cancer that might have been missed by the biopsies(6). This would indicate the need for a targeted biopsy of the suspicious area to ensure that immediate treatment is not necessary. Additionally, MRI can be used for follow-up instead of biopsies, which is much safer and less uncomfortable. Biopsy Planning MRI has already been shown useful for locating prostate cancer when the blood test is abnormal but biopsies are negative. Some physicians have advocated for performing MRI before the biopsy, in order to target the most suspicious area the first time. Not only does this make biopsies more straightforward, but it lessens the likelihood of “undersampling,” the term used when the biopsies miss the aggressive cancer and only find non-aggressive cancer. This risk of undersampling is the basis by which we recommend treatment of nonaggressive prostate cancer, over the concern that more aggressive cancer may have been missed. PROSTATE MRI: INFORMATION FOR PATIENTS AND FAMILIES Biopsy planning is a rapidly developing area. Previously, the MRI images and report would describe the area in question, which the physician performing the ultrasound-guided biopsy would then try to locate using anatomic landmarks. Now, new software is trying to fuse the MRI and ultrasound images, so the physician can see the corresponding MRI images of the needle trajectory. Other centers are developing a dedicated MRI setup for MRIguided biopsies. Focal Therapy Planning Current conventional treatment for prostate cancer consists of chemotherapy including hormonal therapy, surgery, radiation therapy and cryotherapy. New techniques which have been proposed include HIFU (high intensity focused ultrasound, where sound waves agitate and heat tissue, destroying tumor cells), HIFU (high intensity focused ultrasound, where sound waves agitate and heat tissue, destroying FROM PAGE 10 tumor cells) and IRE (irreversible electroporation, where an electric current selectively destroys tumor cells). These techniques are very promising, but none have really gained clinical acceptance, and the last is not yet clinically available. One of the components of these focal techniques, which can pinpoint areas to treat in and around the prostate, is that they require imaging guidance. Because no technique is as good as MRI for delineating the prostate and surrounding tissues and detecting cancer within the prostate, it is the logical choice. MRI has the advantage that it can also measure temperature for both freezing and heating techniques(7). What Does Prostate MRI Involve? The basic physical principles behind MRI have been the subject of two Nobel prizes. MRI takes advantage of the fact that each hydrogen atom functions like its own spinning magnetic compass. By sending a fluctuating magnetic field through a patient and then Combine 5 MRI Techniques for Best Cancer Detection T1 weighted imaging Mainly used to detect hemorrhage T2 weighted imaging Standard “Tissue Contrast” imaging Diffusion-weighted imaging Highly sensitive for cancer detection, but lower resolution Perfusion imaging or Dynamic Contrast Enhancement Localizes cancer based on its disordered blood supply Magnetic resonance spectroscopic imaging (MRSI) Has the poorest spatial resolution, but is the most specific test for identifying aggressive prostate cancer detecting eddies in the resultant magnetic field, one can (using some quite complicated mathematics that involves terms like “inverse Fourier transform” and “spin-lattice relaxation”) generate a picture of the tissues of the human body. Prostate MRI uses this amazing property and adds up to three additional techniques to optimize detection of prostate cancer. T2-weighted imaging is the standard “tissue contrast” imaging we use to identify the prostate and surrounding structures such as the seminal vesicles, bladder, and neurovascular bundles. Cancer and some other conditions appear similar on T2-weighted imaging, so we have to use the other techniques to determine which areas are truly suspicious. T1-weighted imaging is primarily used for detection of hemorrhage, which can confuse the appearance of T2-weighted imaging and diffusion-weighted imaging. Diffusion-weighted imaging uses the principle of Brownian motion, or the movement of free water molecules. Water motion is more restricted in densely packed cells, such as prostate cancer. MRI can use directional pulses to detect the degree to which free water motion is restricted. This has been shown to be highly sensitive for detection of prostate cancer, although it is lower resolution than standard MRI tissue imaging(8). Perfusion imaging, or dynamic contrast enhancement, takes advantage of the fact that MRI imaging is completely safe for patients with normal or near-normal kidney function and no implanted iron or electronic devices. One can repeatedly scan (Continued on page 12) www.PCRI.org • PCRI Insights 11 PROSTATE MRI: INFORMATION FOR PATIENTS AND FAMILIES the same area. When a contrast dye containing the rare earth element gadolinium is injected intravenously, the blood vessels light up. By mapping which areas light up first and brightest, and which wash out earliest, one can localize cancer based on its disordered blood supply(9). FROM PAGE 11 MRI Endorectal Coil Technically, the dynamic contrast enhancement images are also T1weighted, but they are analyzed by a workstation to generate the perfusion maps. Finally, magnetic resonance spectroscopic imaging (MRSI) allows for the measurement of small molecules throughout the prostate. The molecules of interest are citrate, a normal component of prostate cells which is consumed in high metabolic states such as cancer, and choline, which is elevated during rapid cellular membrane turnover, also common in cancer. When the ratio of citrate to choline flips, this is an indication of aggressive cancer. Although MRSI has the poorest spatial resolution, it is the most specific test for aggressive prostate cancer(10). Spectroscopy is tricky. No multicenter study has shown benefit, but many single-center studies at “centers of excellence” have shown benefit from MRSI (12,13,14, 15). Therefore, one should only get spectroscopy done where there are specialists in its use for prostate cancer. Fortunately, dynamic contrast enhancement and diffusionweighted imaging mostly compensate for the lack of spectroscopy in most cases. Some prostate MRI is acquired 12 PCRI Insights • www.PCRI.org MRSI (Magnetic Resonance Spectroscopic Imaging) is the most specific test for identifying aggressive prostate cancer using a special “coil,” which is the name for the antenna that listens to the echoes in the magnetic field. If very high spatial resolution is necessary, a specially designed coil is placed in the rectum adjacent to the prostate. This coil is actually just a loop of wire, but it has a small balloon around it that helps hold it in place. In some cases, mostly those where the lining or “capsule” of the prostate does not need to be accurately outlined and when spectroscopy is not ordered, imaging can be done without the special coil at a cost of some loss of resolution(11). The MRI itself is otherwise relatively uneventful. Most patients will receive an injection of a hormone called “glucagon” in a shoulder muscle which will prevent the rectum from spasming for about an hour. There are no lasting effects of this medicine, but because it can interfere with insulin, diabetics who take insulin must not receive it. Otherwise, one lies on ones back for about 45 minutes. The scan is noisy, but other than the injection of contrast, patients do not feel anything during the exam. It is important that the hips remain perfectly still, as the scans are planned based on the initial images. Prostate Endorectal Coil Because prostate MRI scans consist of multiple components, processing the information can take up to 24 hours. Afterwards, the referring physician will have access to the report and, in most cases, the images. “ offers significantly higher ” signal-to-noise ratio PROSTATE MRI: INFORMATION FOR PATIENTS AND FAMILIES Most insurance, including Medicare, will cover a pelvic MRI with contrast, which is how insurance companies think of prostate MRI. However, many insurance companies (again, including Medicare) will not cover spectroscopy. Spectroscopy is much harder to do well, and there is no simple way for insurance companies to know that they are getting their money’s worth when they pay for it, so in general, they will not. Most imaging centers will allow patients to pay out-of-pocket for this component, but it can cost hundreds of dollars. If it is not covered, the patient and referring physician must decide if it is worth it. How Does One Know If Prostate MRI Is Necessary? Like many medical tests, prostate MRI is ordered by a physician – a patient cannot schedule a scan without a doctor’s order. This is a legal requirement, but it also means that patients must have a discussion with their physician in order to determine if prostate MRI is necessary, and what kind of MRI the physician should order. Prostate MRI is only a part of the diagnosis and management of prostate cancer and is only necessary in specific cases. However, both the technology behind prostate MRI and the understanding of its uses are improving every day, so cases which might have benefitted from MRI in the past might all but require it now. In some cases, the doctor treating the prostate cancer will need to discuss the matter with a radiologist, a specialist in medical imaging, in order to determine what kind of MRI is best and when it would be useful, and to make certain the necessary hardware and software is available. This is a relatively young technology and we are FROM PAGE 12 only beginning to understand how to use it in patient management, but it holds tremendous potential to finally help distinguish patients with non-aggressive cancer who do not need treatment from those with aggressive disease who do. There are certain cases where prostate MRI should not or must not be done. Patients with implanted medical devices, like pacemakers, cannot undergo MRI. Some new device designs purport to be MRIcompatible, but none are commercially available. Patients with metal in their bodies, especially those who have been exposed to welding or “ MRI holds tremendous potential to finally help distinguish patients with non-aggressive cancer who do not need treatment from those with aggressive disease who do. ” lathe work, must be screened for implanted metal in the eyes or other exposed regions. Patients with hip replacements or metal screws in the hips or pelvis can often be imaged, but the metal can cause artifacts on the image, and distort the magnetic field such that diffusion-weighted imaging and spectroscopy cannot be performed. Also, most MRI units have a weight limit, usually between 250-400 lbs. Older high-field magnets often have more stringent weight limits, but low-field and open magnets are not powerful enough to give the kind of information needed for prostate imaging. Finally, patients with kidney failure might not be able to receive contrast, depend- ing on how much kidney function is left. Claustrophobia is a “relative contraindication” as it can often be treated by a sedative prescribed by the referring physician. Most imaging centers are not set up to sedate patients once they arrive, but patients can take medicine prescribed by their referring physicians. REFERENCES 1. Institute NC. Cancer Trends Progress Report – 2009/2010 Update. Bethesda, MD: NIH, DHHS; 2010 [April, 2010]; Available from: http://progressreport.cancer.gov. 2. Partin AW, Mangold LA, Lamm DM, Walsh PC, Epstein JI, Pearson JD. Contemporary update of prostate cancer staging nomograms (Partin Tables) for the new millennium. Urology. 2001;58(6):843-8. 3. Hricak H, Wang L, Wei DC, et al. The role of preoperative endorectal magnetic resonance imaging in the decision regarding whether to preserve or resect neurovascular bundles during radical retropubic prostatectomy. Cancer. 2004;100(12):2655-63. 4. Lawrentschuk N, Fleshner N. The role of magnetic resonance imaging in targeting prostate cancer in patients with previous negative biopsies and elevated prostate-specific antigen levels. BJU Int. 2009;103(6):730-3. 5. Westphalen AC, McKenna DA, Kurhanewicz J, Coakley FV. Role of magnetic resonance imaging and magnetic resonance spectroscopic imaging before and after radiotherapy for prostate cancer. J Endourol. 2008;22(4):789-94. 6. Turkbey B, Pinto PA, Mani H, et al. Prostate cancer: value of multiparametric MR imaging at 3 T for detection--histopathologic correlation. Radiology. 2010;255(1):89-99. 7. Siddiqui K, Chopra R, Vedula S, et al. MRI-guided Transurethral Ultrasound Therapy of the Prostate Gland Using Real-time Thermal Mapping: Initial Studies. Urology. 2010. 8. Desouza NM, Reinsberg SA, Scurr ED, Brewster JM, Payne GS. Magnetic resonance imaging in prostate cancer: value of apparent diffusion coefficients for identifying malignant nodules. Br J Radiol. 2007. 9. Puech P, Potiron E, Lemaitre L, et al. Dynamic contrastenhanced-magnetic resonance imaging evaluation of intraprostatic prostate cancer: correlation with radical prostatectomy specimens. Urology. 2009;74(5):1094-9. 10.Fuchsjager M, Akin O, Shukla-Dave A, Pucar D, Hricak H. The role of MRI and MRSI in diagnosis, treatment selection, and post-treatment follow-up for prostate cancer. Clin Adv Hematol Oncol. 2009;7(3):193-202. 11.Heijmink SW, Futterer JJ, Hambrock T, et al. Prostate cancer: body-array versus endorectal coil MR imaging at 3 T--comparison of image quality, localization, and staging performance. Radiology. 2007;244(1):184-95. 12.Prostate cancer: value of multiparametric MR imaging at 3 T for detection--histopathologic correlation Turkbey B, Pinto PA, Mani H, Bernardo M, Pang Y, McKinney YL, Khurana K, Ravizzini GC, Albert PS, Merino MJ, Choyke PL., Radiology. 2010 Apr;255(1):89-99. 13.M RI in the detection of prostate cancer: combined apparent diffusion coefficient, metabolite ratio, and vascular parameters. Riches SF, Payne GS, Morgan VA, Sandhu S, Fisher C, Germuska M, Collins DJ, Thompson A, deSouza NM., AJR Am J Roentgenol. 2009 Dec;193(6):1583-91. 14.P rostate cancer detection: comparison of T2-weighted imaging, diffusion-weighted imaging, proton magnetic resonance spectroscopic imaging, and the three techniques combined. Chen M, Dang HD, Wang JY, Zhou C, Li SY, Wang WC, Zhao WF, Yang ZH, Zhong CY, Li GZ. Acta Radiol. 2008 Jun;49(5):602-10. 15.P rostate cancer: identification with combined diffusionweighted MR imaging and 3D 1H MR spectroscopic imaging--correlation with pathologic findings. Mazaheri Y, Shukla-Dave A, Hricak H, Fine SW, Zhang J, Inurrigarro G, Moskowitz CS, Ishill NM, Reuter VE, Touijer K, Zakian KL, Koutcher JA. Radiology. 2008 Feb;246(2):480-8. www.PCRI.org • PCRI Insights 13 PCRI Insights, November 2010, Vol 13: No 4 Progress in Prostate Cancer: Targeted Biopsies and Active Surveillance Inderbir Gill, Osamu Ukimura, Mitchell Gross, David Agus C Center for Advanced Robotic & Laparoscopic Surgery and Center for Applied Molecular Medicine USC Institute of Urology, and USC Westside Prostate Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California linically localized prostate cancer is a heterogeneous entity. Prognosis depends upon various factors such as PSA level, clinical exam, and histologic grade (Gleason score). While much of the therapeutic research has focused on the higher-risk patients, the majority of contemporary prostate cancer patients are classified as having a low- or intermediaterisk form of the disease. The long natural history of low-risk prostate cancer and the presence of competing risks in an otherwise elderly male population all contribute to the problem of over-treatment of primary prostate cancer. Herein we discuss our approach for low-risk prostate cancer at the University of Southern California (USC) Institute of Urology focusing on our targeted prostate biopsies and active surveillance as components of our overall program which aims to individualize patient care based on understanding prostate cancer on a “per lesion” as well as a “per patient” basis. Targeted Prostate Biopsies Currently, the standard approach for diagnosing prostate cancer involves performing systematic, non-targeted biopsies (10-12 cores) performed with trans-rectal ultrasound (TRUS) guidance. In routine clinical use, TRUS is used primarily to direct biopsies along loosely defined anatomic regions of the prostate gland (right/left, medial/ lateral, base/mid/apex). A limitation of routine TRUS imaging is its general lack of accuracy to reliably and 14 PCRI Insights • www.PCRI.org reproducibly identify and sample prostate cancer lesions. The limitations of current prostate biopsy strategies are highlighted by studies which demonstrate that in patients with biopsy-proven prostate cancer who are enrolled in active surveillance protocols, repeat biopsies reveal only 40-45% to have the same Gleason score as in their initial biopsy; 30% of repeat biopsies reveal no cancer, and 1520% of repeat biopsies are upgraded to a higher Gleason score [1-2]. It remains unclear if this discrepancy between initial and repeat biopsies represents true cancer progression, or merely reflects sampling error. Many believe it is more likely the latter. At the USC Institute of Urology, we have recently developed an innovative, computer-based prostate biopsy approach which utilizes MRI/TRUS fusionguidance. The approach is based on an ultrasound technology which provides for a 3-dimensional image of the prostate. Except for this specialized ultrasound and computer equipment, the biopsy procedure is otherwise the same (and takes about the same amount of time) as a standard biopsy routinely performed in outpatient settings. Overall, this approach allows us to perform precisely targeted biopsies aimed of suspicious prostate lesions identified on dynamic contrast enhanced (DCE) MRI and/or TRUS imaging. In addition, the precise intra-prostatic location of a given cancer lesion or a needle biopsy location can now be documented with millimeter accuracy. Re-biopsy of the exact location PROGRESS IN PROSTATE CANCER: TARGETED BIOPSIES AND ACTIVE SURVEILLANCE David B. Agus, M.D. Professor of Medicine Director, USC Center for Applied Molecular Medicine Director, USC Westside Cancer Center Keck School of Medicine University of Southern California Dr. Agus’ research focuses on the application of proteomics and genomics for the study of cancer and the development of new therapeutics for cancer, where he develops clinical trials for new drugs and treatments for cancer. Dr. Agus received his M.D. from the University of Pennsylvania. He was a Howard Hughes Medical Institute-NIH Research Scholar, did his medical internship and residency training at Johns Hopkins Hospital, and completed his oncology fellowship training at Memorial Sloan-Kettering Cancer Center. He is the founder of Oncology.com, the largest cancer internet resource/community, Applied Proteomics, and of Navigenics, a health care technology and wellness company. FROM PAGE 14 of a previously positive biopsy site within the prostate is also feasible. In other words, our team now has the ability to precisely record, and re-visit, with high accuracy, any geographical site of biopsy-proven cancer lesion within the prostate. Such capability has hitherto been unavailable. It is likely that such high precision biopsies may allow more individualized decision-making based on “per prostate lesion” data to properly select patients for active surveillance, focal therapy, or radical treatments. Figure 1: The images below demonstrate our targeted biopsy technique based on MRI and TRUS image-fusion guidance. The green lines indicate biopsies that were negative for cancer; the red lines indicate biopsies positive for cancer. Note: Each biopsy is spatially-registered and serially numbered, thus providing intra-prostatic geographic localization [3]. Active Surveillance: Overview The high incidence of clinically occult prostate cancer discovered at autopsy, the side effects of radical therapies, and the low risk of progression following treatment has led to development of less aggressive treatment strategies. “Active surveillance” is an approach incorporating regular clinical follow-up without intervention for select low-risk sub-groups of prostate cancer patients. Several studies have reported on the relative safety, as regards cancer outcomes with relatively short follow-up, for patients treated with active surveillance [4-5]. While there are differences in how patients for active surveillance are selected, generally these studies include patients with very low risk prostate cancer defined by: (Continued on page 16) FIGURE 1: MRI and TRUS Image-Fusion Guidance www.PCRI.org • PCRI Insights 15 PROGRESS IN PROSTATE CANCER: TARGETED BIOPSIES AND ACTIVE SURVEILLANCE low PSA (PSA< 10 ng/ml, PSA density ≤0.15 ng/ml/cm3); low volume cancer; low-grade histology (typically Gleason sum 3+3=6 in ≤ 2 biopsy cores), and low clinical stage (T1c). Similarly, while there are significant differences in how patients are deemed to have “progressed” from active surveillance, a general consensus has developed around factors such as pathologic progression (increase in Gleason score and/or number of cores involved with cancer), rapid PSA progression (defined as short PSA doubling time), and clinical progression on digital rectal exam. In addition, a significant number of patients (25-30%) decide to withdraw from active surveillance and cross-over to radical therapies for various reasons such as “anxiety” or “patient preference.” There exists a need to better define patients enrolled in watchful waiting protocols, by developing a “targeted active surveillance” strategy that incorporates monitoring on a “per lesion” basis rather than the current whole gland approach. Such an approach would possibly be based on spatially-directed biopsy techniques, mentioned above. A New Paradigm: Targeting Prostate Cancer on a “Per-Lesion” Basis We believe that, for patients with low-risk disease, a new paradigm centered around the concept of treatment on a “per lesion” rather than a �whole gland’ basis is attractive. Detailed pathologic study of radical prostatectomy specimens suggests that the prostate typically harbors many geographically defined cancer nodules and genetically distinct clones. Recent evidence suggests that a primary tumor focus, an “index lesion,” is present 16 PCRI Insights • www.PCRI.org is most patients which ultimately drives the natural history of prostate cancer [6]. In most cases, this “index lesion” can be distinguished by its larger size (several-fold larger than secondary lesions) and the presence of aggressive pathologic features such as Gleason pattern 4/5 or extra-prostatic extension. Further support for the concept of an index lesion comes from detailed molecular studies in patients with metastatic prostate cancer, which indicates a monoclonal origin of metastasis in lethal prostate cancer. For example, a study of 94 tumors obtained from 30 subjects who died from prostate cancer indicated that a common pre-cursor cell gave rise to the wide-spread metastasis [7]. The existence of an index lesion has major implications for the care of prostate cancer patients. If an index lesion contains a clone with metastatic potential, it could be targeted and destroyed. Conversely, cancerous areas which do not harbor these “lethal” clones could potentially undergo surveillance without intervention. While some initial efforts have focused on the minority of prostate cancer patients with unilateral or unifocal prostate cancer as potential candidates for sub-total therapies, a more sophisticated approach will be needed to define and characterize the index lesion concept for the majority of prostate cancer patients. We believe that serial “per lesion” monitoring, based on geographically-precise biopsies of cancer lesions, as mentioned above, could provide new insights. Taken collectively, we believe that a greater understanding of prostate cancer on a “per lesion” basis has considerable potential to transform patient care. FROM PAGE 15 Conclusion In summary, we are at a new stage in approaching the diagnosis and treatment of prostate cancer. Technological innovations linking imaging and surgery allow for an unprecedented ability to understand prostate cancer on a “per lesion” basis. This insight will allow for greater diagnostic accuracy and, along a greater understanding of gene and protein changes (genomics and proteomics) which underlie the development and progression of cancer, will allow for a personalized treatment plan for patients diagnosed with prostate cancer. In some patients, conservative therapy consisting of active surveillance may be appropriate. In other patients, interventional therapy with modalities such as minimally invasive robotic radical prostatectomy, radiation, or even focal ablation may be considered. Overall, a new era is ahead where the clinician, the researcher, and the patient will team to get the best outcome for each individual situation. Dr. Agus answers some questions from editor Nathan Roundy 1. Is prostate MRI the �standard of care’ at your clinic? Prostate MRI is standard of care in our clinic for the appropriate patient. The next question would be – who is the appropriate patient. To me, the appropriate patient is not yet defined, but as part of the clinical trial we are doing is all patients who are indicated for biopsy as part of an active surveillance program or are suspected of having a low volume cancer. PROGRESS IN PROSTATE CANCER: TARGETED BIOPSIES AND ACTIVE SURVEILLANCE 2 In Figure 1 you show a targeted biopsy image by itself. Does that mean you would not initial biopsy any prostate area not indicated by MRI? Or do you routinely sample the complete prostate with emphasis on identified suspicious areas? We do traditional expanded sextant biopsies, followed by targeted biopsies of the lesions identified by the dynamic contrast enhanced MRI. 3. Before repeat biopsies, do you also repeat MRI? Yes, we repeat the dynamic contrast enhanced MRI prior to repeat biopsy to fuse with the ultrasound image. 4. Do you only biopsy known lesions on repeat biopsy? We again perform traditional expanded sextant biopsies of the entire prostate, followed by targeted biopsies of the lesions identified by the dynamic contrast enhanced MRI. 5. What MRI technology do you use? 3.0 Tesla? EndoCoil? Diffusion? Spectroscopy? We use a routine 3.0 Tesla MRI with dynamic contrast enhancement and fuse this image with prostate ultrasound. There is no use of an endorectal coil. 6. Regarding your MRI experience, do you have any statistics about sensitivity and specificity? The dynamic contrast enhanced MRI studies were done in collaboration with the University of Lille in France and were able to identify cancer lesions 0.5 cc or greater with an 86% sensitivity and a 94% specificity with an area under the curve of 0.874 [8]. Pretty encouraging for a new technology. 7. For our readers, 86% sensitivity means MRI found the cancer 86% of the time, and only 14% of the time did MRI miss the cancer. And 94% specificity means only 6% of the lesions MRI identified as something unusual, were not identified as cancer. Without going into the statistics, that is basically correct. 8. How long have you been using this targeted biopsy approach in your clinic, and do you have any statistics you can share? We have been using this approach for the past year. It is too early to give exact statistics, but we do have a cancer detection rate in the 60-70 percent range in patients referred (a selected population). 9. Are you accepting patients into this program? If so who do they contact? We are accepting patients into the targeted biopsy program, the robotic laparoscopic prostatectomy program, as well as the care of patients with prostate cancer. For oncology services of Drs. Agus and Gross: 310-272-7640 (USC Westside Prostate Cancer Center, 9033 Wilshire Blvd, Beverly Hills). For targeted biopsy program and the robotic laparoscopic prostatectomy program, Drs. Gill and Ukimura, USC Institute of Urology, (323) 8653707, USC Norris Comprehensive Cancer Center, 1441 Eastlake Avenue, Los Angeles, CA (and beginning January, 2011 biopsies and follow up care will be also at the USC Westside Prostate Cancer Center in Beverly Hills). FROM PAGE 16 10. Would you accept a patient who wanted an MRI, targeted biopsy, and evaluation, but who maybe lives in a distant city and wants follow-up in his home town. How many days would that workup require? Yes, we routinely do both the MRI and targeted biopsy in the same day; requires just a one day stay. We recommend follow up at our clinic for results and arranging follow up care, but realize that this is not always possible and also do telephone consultations for follow up. References 1. Roehl, K.A., J.A. Antenor, and W.J. Catalona, Serial biopsy results in prostate cancer screening study. J Urol, 2002. 167(6): p. 2435-9. 2. Khan, M.A., et al., Can prostate specific antigen derivatives and pathological parameters predict significant change in expectant management criteria for prostate cancer? J Urol, 2003. 170(6 Pt 1): p. 2274-8. 3. Mozer, P., et al., Mapping of transrectal ultrasonographic prostate biopsies: quality control and learning curve assessment by image processing. J Ultrasound Med, 2009. 28(4): p. 455-60. 4. Klotz, L., et al., Clinical results of long-term follow-up of a large, active surveillance cohort with localized prostate cancer. J Clin Oncol, 2010. 28(1): p. 126-31. 5. Tseng, K.S., et al., Risk stratification of men choosing surveillance for low risk prostate cancer. J Urol, 2010. 183(5): p. 1779-85. 6. Ahmed, H.U., The index lesion and the origin of prostate cancer. N Engl J Med, 2009. 361(17): p. 1704-6. 7. Liu, W., et al., Copy number analysis indicates monoclonal origin of lethal metastatic prostate cancer. Nat Med, 2009. 15(5): p. 559-65. 8. Puech, P., et al., Dynamic contrastenhanced-magnetic resonance imaging evaluation of intraprostatic prostate cancer: correlation with radical prostatectomy specimens. Urology, 2009. 74(5): p. 1094-9. www.PCRI.org • PCRI Insights 17 PCRI Insights, November 2010, Vol 13: No 4 Testosterone Inactivating Pharmaceuticals Mark Scholz, MD. P rostate cancer needs testosterone to survive. Blocking testosterone is proven to prolong life in randomized prospective trials. Testosterone Inactivating Pharmaceuticals (TIP), otherwise known as androgen deprivation or hormone blockade, are FDA approved medicines used either alone or with radiation to treat various stages of prostate cancer. Despite widespread experience, there are many controversies about the optimal way to use TIP. Probably the biggest issue is side effects. TIP impacts quality of life. So there is an art to picking the right amount of TIP for each individual. The goal is to continue TIP long enough to get the job done, but stop before going too long. The optimal methodology for using TIP varies from situation to situation because prostate cancer comes in a spectrum of “stages” ranging from low-risk which can be safely monitored without immediate treatment, to metastatic castrate-resistant disease. Between these two extremes are intermediate-risk, high-risk, seminal vesicle invasion (stage T3b), PSA-relapse and lymph-node metastasis (Stage D1). For more details about low, intermediate and high risk disease, see the article titled What’s Your Type available at www.pcri.org. Testosterone Testosterone, the most common androgen in men, is manufactured intracellularly from cholesterol and progesterone, mainly in the testicles. Dihydrotestosterone (DHT), a substantially more potent form of testosterone, is converted from testosterone by the enzyme 5-alpha reductase which is located in the prostate and the liver. Dehydroepiandosterone (DHEA) and androstenedione (ANDRO), weaker androgens, are synthesized in the adrenal glands, located above each kidney. The adrenal glands are where other common hormones such as cortisone and adrenaline are created. DHEA and ANDRO are synthesized from cholesterol and progesterone just like testosterone (see figure 1). 18 PCRI Insights • www.PCRI.org TESTOSTERONE INACTIVATING PHARMACEUTICALS FROM PAGE 18 Figure 1: Synthetic Pathway of Testosterone Cholesterol i Pregnenoione i Progesterone l ( 17oz-Hydroxyprogesterone Dehydroepiadrosterone ( l Androstenedione l ( Estrone Testosterone l ( Dihydrotestosterone Estradiol Prostate cancer can’t survive without testosterone. The prostate gland is a vestigial nubbin until after puberty when it blossoms into a walnut sized gland to manufacture semen. After puberty, if testosterone is removed, the gland involutes and atrophies. Prostate cancer cells are derived from the prostate gland so they also need testosterone to survive. Prostate cancer cells grow and proliferate when testosterone is present; they shrivel and die when testosterone is absent. When testosterone levels in the blood drop, the cancer cells “commit suicide” through a process called apoptosis. They work by suppressing the pituitary gland (at the base of the brain) which in turn sends a suppressive hormonal signal to the testicles. Testosterone Inactivating Pharmaceuticals There are different varieties of testosterone inactivating pharmaceuticals. They fall into three main categories. In the first category are the LHRH agonists such as Lupron, Zoladex, Eilgard, and Vantas. These medicines are administered by injection on a monthly, quarterly, semi-annual or yearly basis. The Hypothalamic-Pituitary-Gonadal Axis In the second category are the anti-androgens such as Casodex, Eulexin and Nilutamide. These pills work at the molecular level to block testosterone from activating the an- drogen receptor (the switch in the cell that enhances cell growth when its turned on). In the third category are the 5-alpha-reductase inhibitors such as Proscar and Avodart. They work by blocking the conversion of testosterone into its more potent analogue, DHT. Combinations These medications can be used together in combination to attain more complete testosterone suppression and thus increase the anti-cancer effect. However, urologists throughout the world more commonly employ single-drug therapy with LHRH agonists alone. This policy is rooted in studies done back in the 1990’s. These studies showed that anti-androgens added to LHRH agonists only enhanced survival by a couple months1 Also many urologists at that time were concerned about the high cost of Casodex. Unfortunately this policy of using LHRH agonists without Casodex persists even though these days Casodex is generic and much more affordable. Adding medicines from the third category, the 5-alpha reductase inhibitors like Proscar or Avodart, is often justified with the rationale that, “It can’t hurt, and it might help.” While using drugs from all three categories is popular in some circles, clinical studies are lacking. There are a number of studies, however, confirming that Proscar and Avodart have an anticancer effect. For more details about using 5-alpha reductase inhibitors to treat prostate cancer, see the article titled Proscar and Avodart at www.pcri.org. (Continued on page 20) www.PCRI.org • PCRI Insights 19 TESTOSTERONE INACTIVATING PHARMACEUTICALS FROM PAGE 19 TABLE 1: Studies Showing Survival Advantage with TIP Author Reference Number Comparison Group Treatment Group Better Survival Bolla 4 No TIP 36 mo. TIP yes Horwitz 5 4 mo. TIP 24 mo. TIP yes Zeliadt 6 No TIP Any TIP yes Granfors 7 No castration castration yes Crook 8 3 mo. TIP 8 mo. TIP yes D’Amico 9 No TIP 6 mo. TIP yes Casodex by Itself Clinicians with experience using Casodex as a single agent, so called anti-androgen monotherapy, have the general sense that: “Casodex monotherapy is about 70% as effective as the LHRH agonists but with only 30% of the toxicity.” Anti-androgens have been studied in prospective randomized trials as stand-alone therapy 2 and combined with radiation. 3 Overall, compared to LHRH agonists, side effects are certainly less. And compared to placebo, they clearly retard prostate cancer growth. The only caveat is a higher risk of breast growth. This can be partially or completely prevented with prophylactic breast radiation or an estrogen blocking pill called Femara. For more details on using Casodex by itself see the article titled Anti-Androgen Monotherapy available at www.pcri.org. 20 PCRI Insights • www.PCRI.org TIP Added to Radiation Improves Survival The most convincing proof that TIP enhances survival is from studies of men with intermediaterisk, high-risk and Stage T3b disease (seminal vesicle invasion) who are undergoing radiation. In the studies, little or no TIP is compared with TIP administered for a more prolonged period. The two groups are monitored over time to determine if one group has superior survival. The results from several such trials are listed in Table 1. As can be seen in Table 1, longer periods of TIP prolong survival more that shorter periods. However, the optimal duration of TIP is still unknown since treatment periods between 8 and 24 months are yet to be tested to see if more than 8 months but less than 24 months would yield comparable benefit. This is an important unanswered question because the side effects Fewer Relapses of TIP can be notable. At the present time our policy is to aim for somewhere between 12-18 months of therapy, depending on how well treatment is tolerated. If side effects are not excessive, a full 24 months of therapy can be considered. For more details on the side effects of TIP see the article Preventing the Side Effects of TIP available at www.pcri.org. Even without radiation, TIP as a sole modality can effectively control prostate cancer for many years. In a prospective trial in men with proven lymph node spread (stage D1), better long-term survival was seen when TIP was started immediately as compared to TIP initiated at the time of cancer progression.10 However, in another prospective trial with locally advanced prostate cancer (seminal vesicle invasion or stage T3b), better survival occurred when radiation was added to TIP, compared to men who were treated with TIP alone.11 TESTOSTERONE INACTIVATING PHARMACEUTICALS To summarize — when the disease is aggressive, TIP and radiation together appear best, but only up to a point. Once the disease becomes metastatic, TIP alone is considered standard. At the other end of the spectrum are the men with intermediate-risk disease. For the more “favorable type” of intermediate risk disease, combination treatment is overkill. These men should be treated with one treatment or the other, not both. Men with the more “unfavorable type” of intermediate risk disease should consider combination treatment, but only with short-term TIP for three or four months. FROM PAGE 20 than 6-9 months).15,16 So more and more experts recommend that TIP be started before the onset of bone metastasis. Recommendations vary when it comes to selecting a predetermined PSA threshold to begin treatment. Numbers like 5, 10 or 20 are suggested as the trigger for starting TIP but other factors, including Gleason score and PSA doubling time, also need to be taken into account. PSA alone fails to portray the whole picture. For example, Johns Hopkins has reported that one-fourth of men with PSA relapse develop bone metastasis with PSA levels under 10.17 Intermittent TIP PSA Relapse Medical experts continue to debate the advisability of starting TIP immediately in men with PSA relapse. The debate is likely to continue because there are no prospective trials, only less definitive retrospective trials.12 The situation is also complicated by differences between patients — some men have relapses that are very slow-paced whereas others have a type of disease that moves faster. And many studies confuse matters by inappropriately jumbling both groups’ together, making outcomes difficult to interpret. Not surprisingly, studies incorporating men with slowly-paced disease show no benefit with starting TIP right after relapse. Such men will do well whether they have TIP or not. To reduce side effects, TIP is often given intermittently.18 The idea of stopping and taking a holiday from TIP was first floated in the early 1990’s. Back then, discontinuing treatment seemed crazy. However, our initial experience with TIP for men in PSA relapse had made us feel pretty upbeat about its effectiveness. PSA levels almost always dropped to zero. With PSA levels so low the question arose, “Have we cured the disease?” The only way to find out was to stop the treatment and see. As it turned out, cure was rare. PSA levels started rising once testosterone in the blood recovered. Even so, we and others were gratified to learn that TIP could be restarted a second time with a high likelihood that the PSA would again drop zero.19 Despite all these conflicting reports, several studies confirm that there is a benefit for starting TIP before the onset of bone metastasis.13,14 This is seen most clearly in studies done in men with faster PSA-doubling times (less Our ensuing experience using TIP intermittently was published in the Journal of Urology.20 We discovered that a longer initial treatment period (up to about 12 months) induced a longer holiday period. Proscar was also shown to further extend the holiday. More recently, we have shown that the off-period can be prolonged further using medicines that work by stimulating the immune system, medicines such as Leukine, low-dose cytoxan, Celebrex and Revlimid.21 For more details, see the article titled Immune Treatment for PSARelapsed Prostate Cancer available at www.pcri.org. Intermediate-Risk Disease In the United States, most men with intermediate-risk disease are treated with surgery or radiation. When radiation is used, adding four to six months of TIP gives better cure rates than radiation by itself.8,9 However, the intermediate-risk category is a broad with predicted post-radiation relapse rates that vary between 10 and 50% depending on the primary Gleason Grade (4 vs. 3), the degree of PSA elevation, and the extent of disease on biopsy. Men with the more “favorable” type of intermediate-risk disease might consider either TIP alone (see below) or radiation alone. Men with the “unfavorable” type of intermediate-risk disease should probably consider using a short-course of four months of TIP plus radiation. TIP Without Radiation I believe that TIP is a reasonable, stand-alone treatment for men with intermediate-risk disease. While there are limited studies documenting its effectiveness (ref), at Prostate Oncology Specialists we have treated 120 men with 12 months of TIP followed by a color doppler directed biopsy of the previously documented cancer site. The biopsy was clear of cancer in 80% of the men. (Continued on page 22) www.PCRI.org • PCRI Insights 21 TESTOSTERONE INACTIVATING PHARMACEUTICALS We have also recently submitted an article for publication detailing the twelve-year outcome of 73 men with an average age of 67 initially treated with TIP alone. The average PSA for all the men was 9. The average Gleason score was seven. Most had a nodule that could be felt on digital rectal examination. Treatment was started back in the 1990’s before the advent of the modern D’Amico staging system (separation of men into low, intermediate and high-risk categories). When we went back and assigned risk-categories (during the process of preparing the publication) men from all three risk-categories were represented. Twenty-one of these men (29%) never needed any further therapy; a single course of TIP kept their PSA suppressed indefinitely. Twentyfour men (33%) required periodic retreatment with TIP (intermittent TIP) to keep their PSA levels under five. Twenty-eight men (38%), rather than continuing on intermittent TIP, decided to have local therapy such as surgery, seeds or radiation. Their local therapy was performed, on average, five and a half years after the first cycle of TIP. Of these 28 men who had delayed local therapy, only three developed a PSA relapse and none have developed metastasis. So clearly, TIP as primary therapy is effective. The problem (as is the case for all prostate cancer treatments) is side effects. Fortunately, after treatment is stopped, testosterone recovers and side effects wear off. Since it is now becoming standard policy to monitor biopsy-positive low-risk disease in a standardized approach called active surveillance, we question why 22 PCRI Insights • www.PCRI.org FROM PAGE 21 active surveillance techniques can’t be used to monitor men with TIPinduced, biopsy-negative disease? Criticisms of using TIP as primary therapy for intermediate-risk disease seem to be based solely on an unwillingness to deviate from “the way things have always been done” rather than any justifiable logic. The Final Word — Quality of Life Testosterone deprivation is one of the most potent treatments ever known for cancer. Breast cancer is the only other hormonally responsive cancer and the antihormones for breast cancer are only 20% as effective as TIP is for prostate cancer. Despite TIP’s potency, quality of life considerations are critical. The side effects of TIP can be severe. When long-term suppressive TIP is indicated, intermittent treatment helps. Men who have locally advanced disease who are taking TIP with radiation for cure, still face uncertainties about the optimal treatment time. The best we can do is weigh impact of the side-effects in each individual and balance them with the known ability of TIP to improve cure rates. References: 1. Maximum Androgen Blockade in Advanced Prostate Cancer: An Overview of the Randomized Trials. The Lancet 355:1491, 2000. 2. Bicalutamide (150mg) Versus Placebo as Immediate Therapy Alone or as Adjuvant to Therapy with Curative Intent for Early Nonmetastatic Prostate Cancer: 5.3 Year Median Followup from the Scandinavian Prostate Cancer Group Study Number 6. The Journal of Urology 172:1871, 2004. 3. Bicalutamide 150 mg Plus Standard Care vs Standard Care Alone for Early Prostate Cancer. Urological Oncology 97:247, 2005. 4. Improved Survival in Patients with Locally Advanced Prostate Cancer Treated with Radiotherapy and Goserelin. The New England Journal of Medicine 337:295, 1997. 5. Ten-Year Follow-Up of Radiation Therapy Oncology Group Protocol 92-02: A Phase III Trial of the Duration of Elective Androgen Deprivation in Locally Advanced Prostate Cancer. Journal of Clinical Oncology 26:2497, 2008. 6. Survival Benefit Associated with Adjuvant Androgen Deprivation Therapy Combined with Radiotherapy for High and Low-Risk Patients with Nonmetastatic Prostate Cancer. I.J. Radiation Oncology 66:395, 2006. 7. Long-Term Followup of a Randomized Study of Locally Advanced Prostate Cancer Treated With Combined Orchiectomy and External Radiotherapy Versus Radiotherapy Alone. The Journal of Urology 176:544, 2006. 8. Final Report of Multicenter Canadian Phase III Randomized Trial of 3 Versus 8 Months of Neoadjuvant Androgen Deprivation Therapy Before Conventional-Dose Radiotherapy for Clinically Localized Prostate Cancer. I. J. Radiation Oncology 73:327, 2009. 9. Risk of Prostate Cancer Recurrence in Men Treated With Radiation Alone or in Conjunction With Combined or Less Than Combined Androgen Suppression Therapy. Journal of Clinical Oncology 26:2979, 2008. 10. Immediate Hormonal Therapy Compared with Observation After Radical Prostatectomy and Pelvic Lymphadenectomy in Men with Node-Positive Prostate Cancer. The New England Journal of Medicine 341:1781, 1999. 11. ASCO 2010: Adding Radiation Therapy to Hormone Therapy Improves Survival in Men with Locally Advanced Prostate Cancer. NCI Cancer Bulletin 7, 2010. 12. Early Versus Delayed Androgen Deprivation for Prostate Cancer: New Fuel for an Old Debate. Journal of Clinical Oncology 23:8225, 2005. 13. Immediate or Deferred Androgen Deprivation for Patients With Prostate Cancer Not Suitable for Local Treatment With Curative Intent: European Organisation for Research and Treatment of Cancer (EORTC) Trial 30891. Journal of Clinical Oncology 24:1868, 2006. 14. Immediate versus deferred treatment for advanced prostatic cancer: initial results of the Medical Research Council trial. British Journal of Urology 79:235, 1997. 15. Early Versus Delayed Hormonal Therapy for Prostate Specific Antigen Only Recurrence of Prostate Cancer After Radical Prostatectomy. The Journal of Urology 171:1141, 2004. 16. Impact of postoperative prostate-specific antigen disease recurrence and the use of salvage therapy on the risk of death. Cancer 116:1887, 2010. 17. Prostate Specific Antigen at the Initial Diagnosis of Metastasis to Bone in Patients After Radical Prostatectomy. Journal of Urology 184:157, 2010 18. Potential Benefits of Intermittent Androgen Suppression Therapy in the Treatment of Prostate Cancer: A Systemic Review of the Literature. European Urology 7:49, 2009. 19. Intermittent Androgen Deprivation in Prostate Cancer Patients: Factors Predictive of Prolonged Time Off Therapy. The Oncologist 5:45, 2000. 20. Intermittent Use of Testosterone Inactivating Pharmaceuticals Using FInasteride Prolongs the Time Off Period. The Journal of Urology 175:1673, 2006. 21. Retrospective evaluation of GM-CSF, low-dose cyclophosphamide, and celecoxib on PSA doubling time (DT) in men with prostate cancer and PSA relapse after surgery or radiation. Journal of Clinical Oncology 28, 2010. PROSTATE CANCER RESEARCH INSTITUTE 5777 W. Century Boulevard, Suite 800, Los Angeles, CA 90045 (310) 743-2116 • Fax (310) 743-2113 • Website: wwww.pcri.org November 8, 2010 Dear PCRI Supporters, More than two million men are afflicted by prostate cancer. Factor in the spouses, significant others, children and immediate family, prostate cancer affects more than ten million people in the U.S. We at PCRI have drawn the line to fight this disease by educating the public, raising awareness, advocating for the patients and supporting prostate cancer research. Several treatment therapies, research and pharmaceutical agents come to market each year. To most patients, these new developments are overwhelming. They are difficult to understand, especially how they impact the patient himself, if at all. Over 200,000 new cases of prostate cancer are diagnosed each year yet there are very few prostate cancer specialists. As a result, patients are not always getting the most reliable and updated information and advice they need to determine the best treatment plan for their specific disease. It is for these reasons that PCRI was established - to educate patients who, sadly, more often than not, rush to treatments that affect their quality of life permanently. PCRI provides cutting-edge, unbiased, and relevant information to its constituency either through its phone-based HELPLINE, quarterly Insights newsletter, www.PCRI.org website and the annual national prostate cancer Conferences. And as most of you know, PCRI provides educational brochures, videos/DVDs, books for practically no-cost to patients, support groups and healthcare providers across the world. Thanks to your friendship and support in years past – PCRI has continued to provide consistent and reliable public service. But we ask that you help us with a generous donation so that we may continue to be a valuable instrument to those who are and will be diagnosed with this dreadful disease. We appreciate your support either through a one-time donation, a recurring donation or by including PCRI in your plannedgiving efforts. Know that your contribution helps us win the fight against prostate cancer! As a token of our gratitude for your generosity, we will send you a copy of the highly successful 2010 Prostate Cancer Conference DVD for donations greater than $149. Please see details in the enclosed coupon. Helpline 800-641-PCRI Sincerely, Chester Swenson President, PCRI Board ® www.pcri.org PCRI QVLJKWV New Developments in Prostate Cancer Treatment Prostate Cancer Research Institute is a 501 (c) (3) not-for-profit public charity www.PCRI.org • PCRI Insights 23 BEST OF THE 2010 PROSTATE CANCER CONFERENCE FROM PAGE 1 Highlights of the Presentations By: Jim O’Hara – PCRI Educational Facilitator Key topics in the talks were amplified in Dr. Moyad’s short Q&A exchange following each talk. One attendee commented: “Questions by Moyad were outstanding! Greatly expanding my understanding”. While most of the questions explored deeper into new concepts presented, one example I noted is that we learned from Dr. Myers where his nickname “Snuffy” originated. Following each talk, the speaker adjourned to a corner of the Exhibit Hall to answer questions from interested attendees. This year, we recorded these “Meet the Speakers” sessions and over 3 hours of Q&A will be available on the conference DVDs. Saturday’s Gala Dinner featured: • A keynote talk by Dr. Mark Moyad (see Lifestyle Modification below) • The presentation of the Harry Pinchot Awards and the Catalyst Award (see separate article) • An inspirational vocal presentation by “America’s Tenor” Steve Amerson Sunday, Dr. Mark Scholz began the program with a recap of key topics from Saturday’s program. This was followed by six breakout sessions for Q&A with a number of experts that allowed direct interaction for attendees. Comments indicated that more of this type of session would be appreciated. Unfortunately, these simultaneous sessions could not be recorded for the DVDs. The conference concluded with a panel discussion involving many of the speakers sharing opinions relating to questions submitted from the attendees. In addition to the educational sessions, many attendees took part in: the four support groups during lunch on Saturday; the “Women Against Prostate Cancer” Breakfast meeting on Sunday; the two Los Angeles Excursions and many casual opportunities to share feelings with others facing similar concerns. Attendees also took advantage of the wealth of 24 PCRI Insights • www.PCRI.org information available from the conference supporters in the Exhibit Hall. You can’t get these experiences from the DVDs. To demonstrate the value some individuals place on attending the conference, I spoke with one man on Friday afternoon. He had just gotten off a plane from the Netherlands. He told me he was returning home after Sunday’s session. The information content from over 20 hours of presentations and Q&A sessions is enormous. I will not try to summarize each talk in this article. The DVDs will provide an opportunity for those interested to grasp the content. I will report some of the key comments made by the speakers that relate to several general topics covered. Please refer to prior issues of PCRI Insights or to the website for the agenda and a list of the faculty. Lifestyle Modification Both Drs. Ornish and Moyad cited the EPIC study (European Prospective Investigation into Cancer and Nutrition) published in 2008 for demonstrating the importance of healthy lifestyle. Exercise, not smoking, eating healthy and healthy weight (waist size) had prevention benefits for Diabetes 93%, heart attacks 81%, strokes 50% and all cancers 36%. Dr. Ornish suggested an optimal diet as low in animal fats but also low in refined carbohydrates. He suggested supplements of Vitamin D3 and fish oil. He mentioned that fiber and bran can fill you up before eating too many calories. Dr. Moyad suggested chia seeds as a good source of fiber and omega-3. 2010 PROSTATE CANCER CONFERENCE SUMMARY Dr. Myers put special emphasis on this by saying that to optimize your treatment outcome “You must do your part!” He mentioned the importance diet and exercise to improve blood pressure, cholesterol and glucose levels. Patients should seek medications to control these if lifestyle changes are not sufficient. He also called for patients to maintain reasonable optimism, to avoid pessimistic physicians and to cultivate a “reason to live”. In addition to monitoring cholesterol, Dr. Moyad suggested hs-CRP (High-sensitivity C-reactive protein) test be done with each cholesterol test. Less than 1 mg/L is considered low risk. In his Active Surveillance talk, Dr. Strum emphasized the importance of life style monitoring and modification. In answer to a follow-up question from Dr. Moyad, he replied that he felt the most important (non-drug) factor is to restrict carbohydrates. Active Surveillance Dr. Strum said the major credit for the current emphasis on Active Surveillance goes to Laurence Klotz MD in Canada. Dr. Klotz has a 450 patient study with average follow-up 6.8 years, an overall survival 78.6% and a 10year prostate cancer actuarial survival 97%. As of 2009, 6 active surveillance studies published all rely on PSA-kinetics and on rebiopsy findings. FROM PAGE 24 When asked if endorectal MRI was better than color Doppler ultrasound for monitoring A/S, he said each has value and may identify problems that the other does not. His advice, select an expert. The following were comments by panel members to a question about using just PSA to monitor A/S. • If there happens to be aggressive cancer present, PSA from prostate cancer may not be a large % of total PSA – a prostatic acid phosphatase PAP test may be beneficial • Additional analysis of the biopsy samples using Aureon Prostate Px+ may be useful – also, Dr. Bonkhoff in Germany can produce a panel of 12 immunohistochemical tests to help determine the nature of the cancer Staging Prostate Cancer Dr. Strum described the evolution of our imaging tools. These have allowed for better staging and the concept of delayed treatment. There was a major setback with the FDA rejection of Combidex®. Several speakers mentioned the value of Combidex imaging done in the Netherlands for their patients. Unfortunately, the manufacturer has discontinued the product but a new product, ferumoxytol, is approved for iron deficiency. Dr. Roach said he expected UCSF would initiate a clinical trial using this with MRI in 2011. • Total patients = 2,168 • Over 200 patients have > 10 years follow up • Overall survival 93% • CSS (cancer specific survival) 99.7% Dr. Strum suggests additional testing be considered for men on Active Surveillance including: • Color Doppler Ultrasound • MRI & MR Spectroscopy • DRE with formal report of findings including capsule and seminal vesicles • Biomarkers PAP, CGA, NSE & CEA • Bone Integrity Reprinted with permission of Dr. Strum (Continued on page 26) www.PCRI.org • PCRI Insights 25 2010 PROSTATE CANCER CONFERENCE SUMMARY Local Treatment Dr. Gil answered a question saying that there should not be a risk of lymphedema after prostatectomy because the lymph nodes removed are not the ones that drain from the legs. Dr. Roach discussed “whole pelvic radiation” for selected highrisk patients. He said that 42% of the pelvic lymph nodes at risk are outside the area that a surgeon samples. He quoted research that suggests an improvement of progression free survival by 2 years without statistically significant increase in grade 3 toxicities. He suggested that temporary implants might be better than permanent if the prostate is large or the tumor extends beyond the capsule. When asked by Dr. Moyad if long-term ADT is required for highrisk patients, Dr. Roach replied that 2 years is the shortest duration of ADT that has shown a survival benefit in random clinical trials. When asked about stereotactic radiation (like Cyberknife®), he expressed concern that the higher dose fractions might cause longterm risk of urethral strictures. He said longer follow-up was needed but questioned “Why choose this when there is 20 year data for brachytherapy?” When asked to compare proton with IMRT, Dr. Roach said there is no reason to believe that proton is better if the dose is the same, also there is no good data that side-effects are less. To a similar question, Dr. Botnick said that image guidance and dose make the difference. 26 PCRI Insights • www.PCRI.org FROM PAGE 25 The following were comments to a panel question about high intensity focused ultrasound (HIFU) •Potency outcomes about 60% – not as good as expected •If prior prostatitis caused calcification, ultrasound is reflected leaving untreated areas Radical prostatectomy, radiation and cryotherapy can all lead to erectile dysfunction. Dr. Mulhall discussed the four main factors that contribute to this condition: cavernous nerve injury, artery injury, erectile tissue damage and confidence erosion. He discussed several ways to address these factors. He stressed the importance of penile rehabilitation after local treatment for prostate cancer to preserve erectile tissue while normal erections are not occurring. Loss of erectile tissue leads to venous leak and permanent function loss. Dr. Mulhall discussed the risks of damage to erection tissue when testosterone is reduced. It appears that 4-6 months of ADT is enough to cause irreversible erectile damage. He suggests ¼ pill of Viagra® at night (as frequently as patient can afford) while on intermittent ADT. Dr. Strum emphasized the importance of stopping the cycle of bone loss with exercise, diet, vitamin D3, boron, calcium and bisphosphonates (if necessary). Castration-Resistant Prostate Cancer (CRPC) Dr. Vogelzang stated that 30,000 develop CRPC each year in this country. Dr. Myers and Dr. Vogelzang both commented that patients should not start chemotherapy until all hormonal treatments (and possibly Provenge) have failed unless there is evidence of extremely aggressive or extensive metastatic cancer. Androgen Deprivation Therapy (ADT) Dr. Myers commented that his goal with ADT is to drive the PSA to < 0.01 as quickly as possible and continue for 12 months. If he is not successful with the usual one to three drugs, he moves directly to second line with combinations of ketoconazole or estrogens. During off-cycles, he suggests options that could increase PSA Doubling Time like Proscar and Avodart, a Mediterranean diet, Celebrex (if medically appropriate), vitamin D3, pomegranate, resveratrol, curcumin. He cautioned when using supplements, it is important to monitor for blood levels and potential side-effects or drug interactions. Dr. Myers updated his results with second-line hormonal therapy using ketoconazole, Leukine and estradiol. He reported a “75% reduction in PSA was seen in 78% of his patients with 49% reaching an undetectable PSA. The bad and good news: After 5 years, it is too early to measure the full benefit.” Dr. Moyad asked why a patient should consider docetaxel when the overall survival advantage is just 2.5 months. Dr. Vogelzang answered that despite the chemo side-effects, quality of life was better and some have much longer survival. Dr. Scholz expanded on this in his summary showing that a 2010 PROSTATE CANCER CONFERENCE SUMMARY 30% PSA decline within 3 months powerfully predicts improved survival. PSA response does not matter to the FDA (even though it is obviously predictive of survival). However, for guiding individual treatment decisions, PSA response is extremely useful. In the Taxotere® trials, the patients whose PSA normalized (less than 4.0) had a huge survival advantage over those that did not. (see slide) Reprinted with permission of Dr. Scholz Dr. Scholz also commented that there are keys to the management of CRPC patients which includes the need to monitor response to treatment closely and if a treatment is not working, move on to something else. • Monitor for at least 60-90 days – PSA, PAP, LDH, ALP tests monthly FROM PAGE 26 PCRI Thanks Supporters and Volunteers PCRI and all of the conference attendees are especially indebted to the many supporters and volunteers who helped to make the 2010 Prostate Cancer Conference possible. These include: Supporters Abbott Laboratories Aureon Laboratories, Inc. Bristol-Myers Squibb Calypso Medical Technologies Daily News Los Angeles Dendreon Corporation Eigen, Inc. Ferring Pharmaceuticals, Inc. Firma Medical, Inc. Foundation for Cancer Research & Education (FCRE) Genentech, Inc. Gen-Probe Inc. GTx, Inc. HealthTronics, Inc. Hitachi, Ltd. iCAD, Inc. Life Extension Foundation Mogreet, Inc. Novartis Oncology Optimum Health Institute Patient Advocate Foundation POM Wonderful, LLC Prostate Institute of America Prostate Oncology Specialists Radnet Inc. Rolling Oaks Radiology sanofi-aventis TheMessengerWines.Com – Pain • Check for the “Small Cell” variant – Check CEA, NSE, CGA every 6 months • Quality of life – Monitor side effects from treatment – Maintain fitness, diet and attitude (no tobacco) Dr. Lam discussed some of the side-effects and stated that the most important concept is to take a break as soon as it is safe. Dr. Moyad mentioned a trial that suggests a benefit in taking ginger before Chemo to reduce nausea. Non-Profit Supporters Malecare Patient Advocates for Advanced Cancer Treatments (PAACT) Us TOO International Women Against Prostate Cancer Volunteers Linda Ball Eileen Call Joan Each Hal Goodman Inge Jones Lynn Lively William Mitchell Robert Mohle Jeremy Scholz Harley Van DeLoo Support Group Leaders Bob Each David and Kathie Houchens Mark Lichty Joel Nowak Erlinda Patterson Finally, Thanks to the 67 attendees who made generous contributions in addition to their conference fees. – Circulating Tumor Cells (CTC) monthly – Bone scans, PET, CT, MRI (every 6 months?) Theragenics Corporation Valley Radiotherapy Associates Vantage Oncology, Inc. Update on Clinical Trials Dr. Vogelzang reviewed the results of several recent and ongoing trials. CALGB 90401: • Addition of bevacizumab (Avastin®) to docetaxel/prednisone/ dexamethasone did not significantly increase overall survival for patients with CRPC • Bevacizumab did significantly improve other clinical outcomes – Progression free survival, PSA decline, incidence of measurable disease • Bevacizumab treatment was associated with more severe toxicities, including death from infections (Continued on page 28) www.PCRI.org • PCRI Insights 27 2010 PROSTATE CANCER CONFERENCE SUMMARY ASCENT 2: • Calcitriol plus weekly docetaxel associated with significantly shorter survival times vs q3w docetaxel in patients with metastatic CRPC  Based on similarity of survival times to other studies of weekly docetaxel, survival effect may be due to weekly docetaxel schedule rather than to addition of calcitriol • Neither protective effect nor reduced toxicity observed with calcitriol plus weekly docetaxel • Weekly docetaxel is not recommended TROPIC: • Cabazitaxel (Jevtana®) was approved by FDA 6/17/10 in combination with prednisone for patients with hormone-refractory prostate cancer previously treated with docetaxel • Cabazitaxel/prednisone (CP) significantly improved overall survival vs. mitoxantrone/ prednisone (MP) in metastatic CRPC • Reduced risk of death: 28% • CP also significantly improved Progression free survival, response rates, and time to progression • Associated with acceptable safety profile – Febrile neutropenia and diarrhea more common with CP vs MP • CP first treatment to demonstrate survival benefit in patients with metastatic CRPC who failed docetaxel-based therapy FROM PAGE 27 • High incidence of adverse events in both arms – More patients who received zoledronic acid experienced acute phase reaction – More patients who received denosumab experienced hypocalcemia – Osteonecrosis of the jaw rare but occurred in approximately twice as many patients with denosumab vs zoledronic acid • Denosumab potential treatment option for patients with CRPC and bone metastases Immunotherapy Several speakers discussed the FDA approval of Provenge® and its availability. Dr. Moyad discussed the current controversy about a delay in approval for payment by Medicare. A petition was circulated to present to the Centers for Medicare & Medicaid Services meeting on November 17th. Dr. Bahn reviewed the “CRITICAL” trial for combined cryotherapy and immunotherapy which is now in process. The FDA approval for the trial is for men who: have proven recurrent cancer in the prostate after organ preserving therapy; are determined to be androgen –independent; with known metastasis limited to three sites and are chemo-naïve. The trial consists of cryoablation of the prostate, followed by injection of a known number of patients’ own immature dendritic cells into the cryoablated prostate with pre-and post-cryoablation low dose cyclophosphamide administration to reduce regulatory T cells temporarily. It is too early to report any findings. • Warnings/precautions: – Neutropenic deaths and mortality related to gastrointestinal symptoms and renal failure reported – Elderly (≥ 65 years) at increased risk of toxicity – Not recommended if hepatic impairment present Denosumab vs Zoledronic Acid: • Denosumab superior to zoledronic acid in delaying or preventing skeletal related events (SRE) in patients with CRPC and bone metastases • No significant difference between treatments in survival or disease progression 28 PCRI Insights • www.PCRI.org Reprinted with permission of Dr. Bahn 2010 PROSTATE CANCER CONFERENCE SUMMARY Future Developments The future looks brighter for prostate cancer patients. With the 2010 approvals of sipuleucel-t and cabazitaxel, physicians have two new weapons against the disease. Dr. Vogelzang expressed optimism for the approval of abiraterone based on a recent news release stating that the Phase III study had been “unblinded” because “based on a pre-specified interim analysis, which demonstrated a statistically significant improvement in overall survival and an acceptable safety profile”. Based on these results, it was recommended that patients in the placebo arm be offered treatment with abiraterone acetate. Additionally, a program will provide early access to abiraterone acetate to patients who meet specified medical criteria is being initiated. [The study is not recruiting at the time of this writing but is listed as NCT01217697 at www.clinicaltrials.gov]. Dr. Vogelzang commented that prostate cancer now has two approved chemotherapies that have demonstrated improved survival. Breast cancer has five. He is enthusiastic about ten other agents are in Phase III trials (see slide). He stated that men must participate in the trials. The higher level of participation by breast cancer patients is one reason for higher funding to breast cancer trials and the larger number of approved treatments. FROM PAGE 28 also described exciting PCF sponsored research at the University of Michigan that has identified 24 types of prostate cancer. This research may provide more effective screening for identifying the men who would likely benefit from treatment and additional ways to define targets for treatments. He also described research at UCLA that has identified four events that occur to turn a prostate cell into a prostate cancer stem cell. Other reasons for hope included the extended survival provided by the new treatments mentioned above and the many brilliant, young investigators dedicated to prostate cancer research. His final reason is the growing patient participation as evidenced by the attendance at the 2010 Prostate Cancer Conference. The Multi-Disc DVD Set of the 2010 PROSTATE CANCER CONFERENCE is expected to ship on December 14th. See coupon for details. (Continued from Page 2, Blue September) The campaign has been a story of success after success, with buildings including the iconic Capitol Records Building, the Ramada Hotel in West Hollywood, the historic Roosevelt Hotel and the Paramount Studio’s Melrose Gate and Water Tower, all bathed in blue light throughout the month. Other key partners to jump on board early include the Oakland Raiders, who dedicated their home season opener to the campaign, and Messenger Wines, who donated proceeds from their biggest selling wine towards the cause. The philosophy behind Blue September is one of positivity and empowerment, using much loved famous faces, looking a little ridiculous in blue paint, and familiar landmarks, with a fun new �blue’ spin, to reach as many people as possible. But the message about prostate cancer is a serious one, with sobering statistics. Prostate cancer affects over 2 million Americans and is chronically underrepresented. Reprinted with permission of Dr. Vogelzang Dr. Jonathan Simons of Prostate Cancer Foundation closed Saturday’s lecture session with a talk titled “Scientific Progress: Top Ten Reasons for Hope”. He listed 23 additional new agents in the pipeline. He Ultimately, Blue September is about changing America’s attitudes and behaviors towards prostate cancer to save lives. For too long the issue has gone unattended, and together the PCRI and Blue September are going to change the face of prostate cancer in America. www.PCRI.org • PCRI Insights 29 PCRI Insights, November 2010, Vol 13: No 4 2010 PCR I AWAR DS At the 2010 PCRI Conference Gala Dinner, PCRI was proud to present awards to three individuals who have given of their time, talents and resources to advance the mission of prostate cancer education and research Har ry P i nc hot Awa r d In honor of the late Harry Pinchot, the Prostate Cancer Research Institute began awarding the Harry Pinchot Award in 2008. Harry Pinchot is best remembered for his extensive knowledge of the biology, prevention, and treatment of prostate cancer. Since his diagnosis in 1995, Harry impacted many patients and their caregivers afflicted by prostate cancer simply with his knowledge and warm spirit. Harry served as PCRI’s Program Director for over a decade, and was known as “Helpline Harry” because of the large number of calls he took from prostate cancer patients. Harry lost his 12 year battle with prostate cancer in January 2008. In his honor, PCRI recognizes unsung heroes who, like Harry, are making a difference in other people’s lives. Men and women can be nominated based on their personal attributes and accomplishments in the fight against prostate cancer through education, research, advocacy, and community support. When we looked at the candidates for this 2010 Harry Pinchot Award, we were aware that two individuals stood out for special commendation – both very worthy of the honor. PCRI is proud to present 2010 Harry Pinchot Awards to Johnny Payne and Howard Hansen. Johnny Payne has been described as a visionary, an activist, a motivator, a mentor, and an inspirer. He is a prostate cancer survivor, a listener – one who “has been there”. He learned (and continues to learn) all there is to know about prostate cancer and uses that to help African American and all other men with prostate cancer. He is responsible for coordinating screening of over 1000 men annually, and giving more than 30 seminars that reach over 1500 men annually. He formed collaborations 30 PCRI Insights • www.PCRI.org 2010 PCRI AWARDS FROM PAGE 30 with health systems and hospitals; with Us TOO, American Cancer Society, Zero and the South Carolina Cancer Alliance; with men’s fraternities and over 100 churches in his area. He has spread the word across local media and has earned several prestigious awards, including WJMZ Black History Maker, Omega Psi Phi Organization of the Year, and the Us TOO Edward Kaps Hope Award. If that isn’t enough, he is founder and Executive Director of Upstate Prostate Cancer Alliance. In accepting the award, he said: “— the mission is to make a difference – we want to put pressure on our legislators to pass favorable legislation so we can get funding to defeat this disease, find a cure and if not necessarily a cure, find a better screening method… that perhaps will end this “To screen or not to screen” controversy.” Bruce Laumeister, HRPCa treasurer, accepted the award for Howard and presented it to him at his home in Vermont. Howard Hansen is the co founder of the Hormone Refractory Prostate Cancer Association (www.hrpca. org) and has been helping patients with their disease for 16 plus years. Using his advanced web site and his extensive research into many medical journals, he has given advice, assistance, and encouragement to hundreds of patients with the more severe hormone refractory prostate cancer. Howard’s compendium of treatment options is available on his web site and is constantly updated. (Continued on page 32) How to Contribute to PCRI Direct Donations Cash, check, or credit card; stock or real estate. Memorials Honor a loved one with a memorial or commemorative gift in their name. Payroll Deductions Federal employees can contribute to the Combined Federal Campaign in their workplace. Look in the Cancer Cures section of the CFC directory orc all PCRI for the number. Planned Giving Naming PCRI in your will or as beneficiary of your IRA or life insurance policy. Planned Giving Opportunities For information on Planned Giving opportunities or how to put PCRI in your will, please contact PCRI at (310) 743-2116, or by e-mail at: [email protected]. Please Donate Today Your tax-deductible gift of cash,stocks or real estate, as well as Gifts in Honor and Memorial Gifts, should be made payable to PCRI and mailed to: Prostate Cancer Research Institute Gifts in Honor and Memorials 5777 W. Century Blvd Suite 800 Los Angeles, CA 90045 A gift to the PCRI is a special way to give tribute allowing individuals, organizations, businesses and groups to honor someone while supporting PCRI’s mission. Credit card donations can be made at www.pcri.org or by calling (310) 743-2116. www.PCRI.org • PCRI Insights 31 2010 PCRI AWARDS FROM PAGE 31 A diagnosis of HRPC is a serious development for the family fighting prostate cancer. It often comes accompanied by an uncertain prognosis that adds an emotional burden. Hansen and all of the volunteers working on the HRPCA Web site have been through this experience. Without exception, they have chosen to reject defeat and to fight this disease with their time, their ingenuity, their resources, and their computers. Even when suffering from severe metastatic prostate disease, Howard continued to be available for the many men in the Hormone Refractory Prostate Cancer web group. Howard’s stamina and endless assistance to others is an inspiration to us all. He acquired the nickname of “Helping Howard”. In an emotional acceptance speech, Howard’s friend Bruce Laumeister emphasized: “- his incredible ability to translate this incredible information into things to guide people as to what to do next … this man has saved so many people all over the world” (Editor’s note: Unfortunately, we received word on October 5th that Howard had lost his battle with prostate cancer. Howard joins Harry Pinchot, 2008 award winner Bill Blair and several others in memory as those who unselfishly helped so many of us in this battle.) T he PCRI Catalyst Award was established to highlight the outstanding work and generosity of individuals and organizations that set the standards for bettering the lives of those with prostate cancer and their families. The recipient is chosen by the PCRI Board of Directors, and is a person that PCRI considers “ an agent of change” who has shown a history of leadership, philanthropic involvement and educational commitment within the field of prostate cancer. PCRI is thrilled to present the second annual Catalyst Award to James R. Warren II. James R. Warren II is recognized for his generosity in providing financial resources that support and strengthen prostate cancer education and exciting research. His support could potentially help millions of men by inhibiting or treating prostate cancer and that could significantly improve patients’ quality of life. 32 PCRI Insights • www.PCRI.org James Warren was raised in San Diego, California and currently resides in Kailua, Hawaii with his wife Michele. He graduated from the University of California, Santa Barbara in 1976 with a B.S. degree in Biological Sciences, and is also an alumnus of the Harvard Business School. In 1978, he became a Founding Partner of Kinko’s Copies and served as the company President for ten years. He currently serves on the Board of Trustees for the University of California at Santa Barbara Foundation. James enjoys traveling, cooking, tennis, body surfing and spending time with his children. James Warren could not attend the conference but in a video acceptance, he stated: I would like to take this opportunity to thank the dedicated doctors and healthcare professionals involved with this conference. … These conferences have provided me with lots of information and I have always been impressed with the knowledge of the attendees so I look forward to attending next year’s conference and I hope everyone considers supporting PCRI.”
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