nsights AUGUST 2006 VOL 9: NO 3

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1 PCRI nsights Patient & Physician in Co-Partnership AUGUST 2006 VOL 9: NO 3 New Developments in Prostate Cancer Treatment Attention: Men with Recurrent and Advanced Prostate Cancer This fall, for the first time, a full-scale regional conference entitled, Improving Treatment and Quality of Life, will address your needs. The PCRI has assembled a firstclass faculty to provide you with the latest information and answer your questions if you are threatened or already dealing with: A recurrence of PC after primary treatment (such as surgery or radiation) Cancer that has escaped the prostate PC that has spread to the lymph nodes or bones A rising PSA while on testosterone deprivation therapy Erectile Dysfunction Urinary Incontinence The day begins at 7:30 with registration and a continental breakfast in the Golden Eagle Ballroom at California State University Los Angeles on Saturday, September 9, with the following nine hours filled with information specifically addressing the urgent needs of men with recurrent and advanced PC. This is an opportunity you can t afford to miss! You get the whole day for just $35 per person, which includes parking, a continental breakfast, lunch, and a program, not to mention all of this information. In every sense, this is a conference designed specifically for you, although it may also be of great interest for your family, and your doctor. So use the convenient registration form on page 15 or register online at Program and Registration on page 15 ABOUT THE MEDICAL ARTICLES IN THIS ISSUE Gleason Grade Migration (Page 2) David Luthringer,MD and Mitchell Gross,MD,PhD Gleason grade migration refers to the observation that prostate cancers are commonly graded higher today,in the contemporary era, than in previous times, resulting in the diagnosis of a greater percentage of more aggressive cancers. This article draws on studies and experience at the Cedars-Sinai Medical Center to evaluate Gleason grade migration. Studies show a shift toward higher Gleason scores apparent over the last years.this migration is important because of the impact of the Gleason Score on widely used clinical measures such as the risk of the cancer recurring after treatment or dying as a direct result of the disease. PCA3: A Genetic Marker of Prostate Cancer (Page 4) Alejandra B. Torres and Leonard S. Marks, MD Of approximately four men with elevated PSA levels who undergo prostate biopsies, only one will be found to have the disease. Moreover, some cancers in men with normal PSA levels escape detection with the PSA measurement. Another marker is needed,and the urinary PCA3 gene test may well be that marker. Early studies indicate this new marker has a much greater degree of PC specificity than PSA testing. In recent clinical trials from Canada and Austria, the potential diagnostic value of the PCA3 urine test was soon established.in these two trials, more than 700 men who were undergoing prostate biopsy donated urine after attentive digital rectal exam. When the urinary sediment contained enough prostate epithelial nuclear material to be evaluated, the PCA3- to-psa mrna urinary levels exhibited a 66-82% sensitivity and a 76-89% specificity for cancer. Both values compare quite favorably with accuracy of PSA. The authors caution that while the early data look promising, the PCA3 test must still be regarded as a work in progress albeit a very promising one. Highlights of the EAU Congress (Page 10) By Douglas Chinn, MD In April 2006, Dr. Chinn attended the 21st annual meeting European Association of Urology (EAU) in Paris. This meeting is the largest urological meeting in Europe, and the second largest in the world. This year,dr.chinn reported,prostate cancer was one of the four primary topics, and several papers challenged the common wisdom of PC treatment. Dr. Pierre Telliac provided a new look at thecomparative incidence of impotency from radical prostatectomy (RP) and brachytherapy over time, and also, in addressing PSA screening, he commented, There is never such a thing as too much knowledge, and prostate cancer screening by PSA and diagnosis by biopsy simply provide valuable knowledge. Professor Guy Vallencien presented a provocative paper pointing out that much of the confusion of outcome data is due to the non-standardized collection and assessment of the preand post-operative information. This contributes to the varied outcome data results, so that the data was like the Tower of Babel. Even Dr. Peter Scardino surprised everyone when he actually discussed and promoted focal therapy as a therapeutic treatment in highly selective patients, as an alternative to watchful waiting with delayed intervention.

2 Gleason Grade Migration: Changes in Prostate Cancer Grade in the Contemporary Era Daniel J. Luthringer, MD and Mitchell Gross, MD, PhD Departments of Pathology and Medicine, Cedars-Sinai, Los Angeles Introduction Tumor grade refers to the microscopic appearance of cancer tissue obtained after a biopsy or surgery as determined by a pathologist. For prostate cancer patients, tumor grade (along with clinical stage and PSA) is particularly important in determining prognosis and aids patients and physicians as they make important treatment decisions. The dominant grading system used for prostate cancers is named for its inventor, Dr. Donald Gleason. In 1966, Dr. Gleason proposed a grading system for prostatic carcinoma that was based solely on architectural features of the tumor. The Gleason scoring system identifies five different patterns of cancer, (i.e. assigns a number from 1 to 5), based on how close to normal (differentiated) the cancer looks under the microscope. Gleason pattern 1 is the most differentiated (or benign appearing) pattern. Gleason pattern 5 is the most de-differentiated (or aggressive appearing) pattern. Prostate cancer is almost universally present in multiple parts of the gland and often has a different microscopic appearance (different Gleason patterns) in different areas of cancer. Therefore, the original description of the Gleason grading system included adding the numbers assigned to the most prevalent and second most prevalent patterns to result in a Gleason score (or Gleason sum). The Gleason score (ranging between 2 and 10) ultimately comprises the tumor grading used in prostate cancer. For example, if a pathologist observes a moderately well-differentiated area of cancer (Gleason 3 pattern) as both the most common and second-most common area in a specimen, the final Gleason score assigned would be 6; derived from 3 (most prevalent) + 3 (second most prevalent) = 6. The Gleason grading scheme was widely adopted in North America through the 1980s and 1990s, after numerous studies firmly established that it served as a 2 PCRI INSIGHTS vital pathologic predictor for disease outcome. In 2003, recognizing the importance of the Gleason grading system, the World Health Organization (WHO) endorsed Gleason grading as the standard for prostate carcinoma. The Gleason grading system continues to play a critical role in the management and treatment stratification of patients with prostate cancer. Gleason Grade Migration Gleason grade migration refers to the observation that prostate cancers are today commonly graded higher, in the contemporary era, than in previous decades, resulting in a greater percentage of higher grade prostate cancers. 1 A number of studies have evaluated Gleason grade migration and its impact on important clinical measures such as the risk of the cancer recurrence and cancer-related deaths (prostate cancer specific mortality). Albertsen et al 2 analyzed a group of 1858 cases of prostate cancer. The cases were drawn from a sample of all men diagnosed with prostate cancer between 1990 and 1992 in the state of Connecticut. With the patients permission, clinical information was entered into a database, and microscopic slides from their original biopsy (obtained and read in ) were re-read in 2004 by a different, highlyexperienced pathologist who was blinded to the original Gleason score. This study showed that the average Gleason score increased from 5.95 to 6.8 when comparing the original reading to the contemporary reading. Importantly, in 55% of the cases, the Gleason score was upgraded by one point or more. Therefore, this reassessment demonstrates a definite shift to higher grade prostate cancers, when a contemporary pathologist reads the same specimen that was read years ago. Ultimately, the importance of the Gleason score is to predict which patients have the most aggressive forms of prostate cancer. Therefore, it was important to determine if changing the Gleason score altered its ability to predict patient outcomes. When the contemporary Gleason scores were used and the patients grouped by Gleason scores, the authors reported that the every group of patients did significantly better with the contemporary over the original Gleason score. The prostate cancer outcomes for the entire group of patients were identical regardless of which Gleason grade ( contemporary or original ). Therefore, this study demonstrated an inflation or upward migration in Gleason scores occurring over time. When the effects of this reclassification were combined for all groups and standardized for differences in the number of patients with particular Gleason scores, the re-grading resulted in a 26% reduction in prostate cancer specific mortality compared with the same patients as graded by the original pathologists. Therefore, one important effect of Gleason grade inflation is to make patients diagnosed in the current era appear do better than historical controls when statistically adjusted for differences in Gleason scores. Similar observations were made by Kondylis 3 et al who re-examined 100 cases of prostate cancers and compared this data with original grades and outcomes. A significant upward grade migration from the historic to the current grade was observed, causing deviations in the cancer-specific survival curves. In a study of 983 radiated prostate cancers, Chism et al 4 found a systemic Gleason score upgrading of cases in the 1990s that they attributed, at least partially, to an improved 5-year biochemical relapse-free survival. Smith et al 5 reassessed a series of patients treated by surgery, in which the Gleason scores, on review, proved to be significantly higher than a decade before. In a series of prostate cancers treated with brachytherapy, Schellhammer et al 6 also demonstrated a

3 GLEASON GRADE MIGRATION: CHANGES IN PC GRADE IN THE CONTEMPORARY ERA FROM PAGE 2 significant upgrading of the Gleason scores over original scores of 15 years earlier. Cedars-Sinai Experience Anecdotally, and as unpublished observations,we have experienced a Gleason grade migration at our own institution. Looking at the biopsy diagnosis of prostate cancer incrementally in blocks of time from 1993 to1998 (n=264), 1999 to 2001 (n=292), and 2002 to 2005 (n=729), we observed a shift away from lower grade cancers diagnosed with Gleason score less than 6 (see Figure 1). In the 1993 to 1998 time period,these low score cases represented over 20% of all cases at the time of initial diagnosis. No cases of Gleason score less than 6 were diagnosed in the 2002 to 2005 time period.similarly,the percentage of higher grade Gleason scores (scores 8, 9 or 10), shifted from about 3% to almost 10% of biopsies. Observations of the 2002 to 2005 time frame are important in the understanding of the grade shift.in 2002,prostate cancer was read by a small team of three pathologists primarily devoted to this part of the body. This was a dramatic change from upward of 16 inter-generational pathologists in previous years. The group of three focused significant attention on the contemporary understanding and application of the Gleason grading system, undoubtedly contributing to the observed grade migration. 70% 60% 50% 40% 30% 20% 10% 0% In summary, our observations appear to confirm a trend to the upgrading of prostate cancers using the Gleason grading system and, as described in the studies above, may result in the appearance of improved outcomes for prostate cancer patients. Factors Contributing to Gleason Grade Inflation There are several factors that are thought to explain the phenomenon of Gleason grade inflation. Pathologists may increasingly be swayed to incorporate a slight modification of the Gleason grading system itself. As initially described, pathologists were only supposed to include the two most common patterns in the Gleason score. However, there is increasing evidence suggesting that presence of a third (tertiary) Gleason grade higher than the primary or secondary component is important, and should be reported. 7,8 Pathologists may want to include a small amount of high-grade cancer in the Gleason score. As described below, new recommendations will actually mandate this change. Although not part of the classic grading system, this reinterpretation may explain some measure of grade migration. Another explanation is the learned experience of pathologists with the system Prostate Biopsies GS<6 GS=6 GS=7 GS=8 GS=9 GS=10 Gleason Score Figure 1. Changes in Gleason scores observed at Cedars-Sinai Medical Center between 1993 and acquired over time. Many studies 9,10 have demonstrated that Gleason scores obtained from biopsies are frequently upgraded on prostatectomy specimens, most likely as the result of sampling error. This makes sense when you realize that only a very small portion of the prostate is analyzed by biopsy compared with the entire gland analyzed at the time of surgery. The idea is that through many years, the discrepancy between biopsy Gleason grade and surgical Gleason grade has pressured pathologists, in the case of borderline or questionable biopsy cases, to up-grade cancers, knowing that in a significant number of cases, the patient most likely has higher grade cancer lurking in his prostate gland. Along with these factors which drive finding more higher grade cancers, there are also factors leading to a decreased incidence of lower grade cancers as well. The lowest Gleason grades (1 and 2) are generally found only in the central portion of the prostate. The central core of the prostate around the urethra, the central zone, is generally not amenable to sampling using the current biopsy techniques. Hence, recommendations have been widely published 9,11 which strongly discourage pathologists from diagnosing lower grade cancers on transrectal biopsies. Further, modern pathologists often use more sophisticated techniques to examine specific proteins in cancer tissue (immuno-histochemistry). By using this technique, it is thought that many cases of Gleason 1 cancer were actually an abnormal benign growth in prostate tissue ( adenosis ) which mimics cancer, but is not actually malignant (i.e. does not grow and spread outside of the prostate). Changes to the Gleason Grading System Much has changed since the Gleason grading system was developed 40 years ago. Based on changes in the way prostate cancer is diagnosed and treated, modifications to the Gleason grading system have continued on page 9 PCRI INSIGHTS 3

4 PCA3: A Genetic Marker of Prostate Cancer Alejandra B. Torres* and Leonard S. Marks, MD* David Geffen School of Medicine at UCLA, Los Angeles, CA *Urological Sciences Research Foundation (USRF) and Department of Urology Introduction The advent of molecular diagnostics has brought the promise of a specific test for prostate cancer PC, the urinary PCA3 gene test. Widespread testing with prostate-specific antigen (PSA) has increased the numbers of prostate biopsies to perhaps one million annually in the U.S. However, serum PSA levels are not specific for PC. Thus, of approximately four men with elevated PSA levels who undergo prostate biopsies, only one will be found to have the disease. Moreover, some cancers in men with normal PSA levels escape detection with the PSA measurement. Another marker is needed, and the urinary PCA3 gene test may well be that marker. Early studies indicate this new marker has a much greater degree of PC specificity than PSA testing. Limitations of PSA Testing for Prostate Cancer Within the prostate gland, benign prostatic hyperplasia (BPH) cells contain a concentration of PSA several-fold higher than that of adjacent cancer cells. 1 This seriously undermines the theoretical basis of PC testing with PSA.With data from the Prostate Cancer Prevention Trial, where biopsies were obtained irrespective of PSA levels, Thompson has shown that There is no cutpoint of PSA with simultaneous high sensitivity and high specificity for monitoring healthy men for prostate cancer, but rather a continuum of prostate cancer risk at all values of PSA (Table 1) 2. And Stamey, an early advocate of PSA testing, has declared, Serum PSA levels are no longer related to prostate cancer, but only to the volume of BPH present 3. Why? Because the disease has changed! Nowadays, instead of finding large primary cancers in the prostate such as was seen 20 years ago, the usual findings are multiple small lesions, where the serum PSA contribution to the prostate cancer is overwhelmed by the BPH contribution (Figure 1). Despite these changes, nearly 30,000 men will still die of PC this year, so an accurate test for the disease is an urgent priority. The major foibles of PSA testing for PC were recently detailed in a USRF website posting ( 10Foibles_of_PSA/index.htm). Figure 1. Diagram showing effect of PSA testing, which began in the mid-1980s, on volume of index (largest) cancer in the prostate over ensuing decades. The index cancer volume has progressively decreased. In data from Stanford University, volume of the average index cancer found at radical prostatectomy has decreased from 5.3 cc to 2.4 cc over the past 20 years, mainly because of increasingly early diagnosis. 3 Figure 2. Northern blot analysis using probes for DD3,now called PCA3 (upper lane) and PSA (middle lane),with rrna (28S) as a control (lower lane). Ten loaded per lane. Numbers 1-14 refer to different patients whose mrna was studied in the analysis. Tissues studied: T=tumor, B=benign prostatic hyperplasia, N=normal, N/T=normal+10% tumor cells, and M=metastasis. Over-expression is determined by comparing the intensity of the bands. Note that the PSA mrna does not distinguish normal from tumor tissues, whereas DD3 (PCA3) is clearly over expressed in tumors. Reproduced from M.J.Bussemakers,et al,cancer Res.59: 5975,19994 (with permission). Table 1. Sensitivity and Specificity for Prostate Cancer by Cutpoints of Prostate Specific Antigen (PSA). 2 Any Cancer (n=1225) vs. No Cancer (n=4362) PSA, ng/ml Sensitivity Specificity Discovery of the PCA3 Gene In the early 1990s, at about the same time that PSA testing was starting to gain widespread adoption, a young molecular biologist from Holland began post-doctoral work at The Brady Urological Institute of Johns Hopkins University. There, in the laboratory of William B. Isaacs, Marion Bussemakers performed studies on human prostate tissue using the technique of differential display, a then newlydescribed method to identify gene expression in different tissues. During this series of experiments, an mrna was discovered that appeared to be highly specific for prostate cancer (Figure 2) 4. This gene could not be found in any of the existing gene databases. Bussemakers and Isaacs called their new gene DD3, referring to its appearance in the display, and they concluded that it might be useful in prostate cancer detection. The gene was ultimately found to be over-expressed in 53 of 56 prostate cancers and absent from 18 other normal human tissues. Further study revealed the new gene to be a noncoding RNA, which could be mapped to chromosome 9q21-22 (Figure 3). DD3 was initially described in 1994 at the Congress of the European Society for Urolological Oncology and Endocrinology in Berne, Switzerland. Further development of PCA3 was performed in the laboratories of Jack A. Schalken, Bussemakers supervising professor at University Hospital, Nijmegen, 4 PCRI INSIGHTS

5 PCA3: A GENETIC MARKER OF PROSTATE CANCER FROM PAGE 4 Figure 3. Hybridization of metaphase chromosomes of human lymphocytes, using a DD3-specific probe, shows that DD3 is mapped to chromosome 9q21-22 (arrowhead) 4. the Netherlands. Among the important contributions from Nijmegen were the first clinical demonstration of the specificity of PCA3, its measurability in urine, and the importance of denoting PCA3 expression vis-á-vis a background of normal prostate epithelial genetic material. 5,6 Interest in urinary prostate cells, which had been generally abandoned years before, was then resurrected, and urinary PCA3 research studies were soon instituted by Yves Fradet in Laval University in Canada. A prototype urine assay known as upm3 was developed at DiagnoCure. During this time, the nomenclature for DD3 was formally changed to PCA3. Why Molecular Markers? Molecular biology may be defined as the branch of biology focused on the formation,structure,and function ofdna, RNA and proteins, and their roles in the transmission of genetic information. The central theme of molecular biology is as follows: Information encoded in a sequence of the DNA strand passes to molecules of RNA through a process called transcription. The RNA acts as a messenger (mrna) to pass the information to proteins through a process called translation. The message transcribed from the gene is therefore translated into a protein product that is specialized for a particular function based on the instruction stored in the gene. With the sequencing of the human genome, molecular biologists faced another hurdle: determining the function of individual genes and their protein products. Knowing the function of each gene is essential to biotechnology, which is a branch of engineering that focuses on using such knowledge for the development of molecular markers and treatments for diseases such as prostate cancer. Thus, a gene is the fundamental unit of storage and transmission of cell biology. To know the genetic make-up of a biological unit is to know the potential direction of its development. How genetic information is passed and how cancer may develop when this process goes awry is shown in online videos from the National Cancer Institute ( Initial Clinical Experience with PCA3 While the PCA3 gene was clearly discovered in Isaacs s lab at Johns Hopkins, the Netherlands is where the gene was initially translated from lab to clinic. 5,7 The earlier work of Bussemakers and Isaacs was confirmed and expanded at Schalken s institution in Nijmegen. A method to accurately quantify the gene in urine was developed, using the RTqPCR gene amplification method. Receiver operating characteristics for PCA3 (tumor vs. benign cells) were shown to be remarkable, with a area under the curve (AUC), i.e. the accuracy of the test at the cellular level was nearly perfect. The median upregulation of PCA3 from normal to tumor tissue was found to be 34- fold 5, increasing to 66-fold in tumor tissue containing more than 10% cancer cells 7.This upregulation in cancer tissues provided a theoretical basis for detecting the presence of the gene in tissues containing only a small number of cancer cells, against a background of low expression by many normal or BPH prostate cells, i.e., in tissue biopsies and bodily fluids 5. Thus, the importance of denoting PCA3 as a ratio with PSA mrna (a surrogate for background prostate epithelial cell nuclear material) was established. Equally important, a practical application was confirmed: the PCA3 ratio determined in voided urine,especially after light prostatic massage, or attentive digital rectal exam, was shown to be a sensitive and specific test for PC in the host. 7 In recent clinical trials from Canada 8 and Austria 9,the potential diagnostic value of the PCA3 urine test was soon established. In these two trials, more than 700 men who were undergoing prostate biopsy donated urine after attentive digital rectal exams. When the urinary sediment contained enough prostate epithelial nuclear material to be evaluated, the PCA3-to-PSA mrna urinary levels exhibited a 66-82% sensitivity and 76-89% specificity for cancer. Both values compare quite favorably with PSA accuracy. However, using the early assay method, approximately 15%-20% of PCA3 samples were deemed non-evaluable because the urine did not contain a sufficient quantity of PSA mrna to allow detec- continued on page 6 PCRI INSIGHTS 5

6 PCA3: A GENETIC MARKER OF PROSTATE CANCER FROM PAGE 5 tion of background genetic material. Evolution to Present-Day Test In the clinical trials cited above, gene testing was performed at DiagnoCure, a Canadian biotech company founded by Dr. Yves Fradet. Fradet had obtained the PCA3 patent from the group at Nijmegen. The gene was then known as upm3, and the test was a qualitative assay. In November 2003, Gen-Probe, Inc of San Diego, CA acquired from DiagnoCure exclusive worldwide diagnostic rights to this new prostate cancer gene, which is now known, according to standard nomenclature, as PCA3. Gen-Probe soon developed a quantitative PCA3 molecular assay employing the technologies of Target Capture, Transcription Mediated Amplification (TMA), and Hybridization Protection (HPA). (Figure 4). 10 In collaboration with Urological Sciences Research Foundation (USRF) of Culver City, CA, clinical testing of the Gen- Probe assay began in early 2004, and the first presentation of data from that work was made at the Gordon Research Conference on Biomarkers in January, The PCA3 test is actually a dual assay in which both PCA3 and PSA mrna are separately quantified and the ratio of the two, the PCA3 Score, is determined. The ratio is used because the denominator, PSA mrna, establishes the amount of prostate-specific nuclear material in the specimen.a low level of PCA3 is expressed by normal prostate cells, and if absolute concentration of PCA3 were used, a high Score might be obtained from a specimen rich only in normal prostate cells. Thus, the PCA3 Score tells the expression of PCA3 corrected for the background of normal or BPH epithelial cells present in the specimen.(figure 5).In early clinical testing, it was soon determined that the higher the urinary PCA3 Score, the greater the likelihood of prostate cancer. (Figure 6). In addition to normalizing the PCA3 signal, measurement of PSA mrna also serves to confirm that the yield of prostatespecific RNA is sufficient to generate a valid or informative test.without a certain minimum amount of prostate-specific genetic material in the sample, the test is deemed non-informative. An attentive digital rectal exam (three sweeps on each side of the prostate), performed just prior to urine specimen collection, improves the informative rate from approximately 80% to greater than 95%. it is likely that the informative rate now being obtained with the new assay is attributable to both the attentive DRE and the increased sensitivity of the new assay technologies explained above. Current Use and Availability of PCA3 Testing In presentations at the 2006 American Urological Association meeting (J.Urol., 175: (S), 2006), in recent data gath- continued at right In step No.1 (top), target capture of the mrna is performed, using magnetic bead (purple). In step No. 2, the captured gene is amplified using Transcription-Mediated Amplification, a process that generates some 10 billion copies of PCA3 in one hour. In step No. 3, the Hybridization Protection Assay is performed using DNA probes tagged with a chemiluminescent substance that is activated upon contact with detection reagents. Details of the assay are described in a recent publication 10. Figure 4. Distinguishing features of the PCA3 assay (Gen-Probe, Inc.) are shown in sequence. Figure 5. Diagram showing that a background low level of PCA3 expression is present from the benign prostate cells in urine (left). On right, a single cancer cell is shown to greatly over-express the gene, allowing detection in a urine specimen of an abnormal quantity of PCA3 relative to the normal background. 6 PCRI INSIGHTS

7 PCA3: A GENETIC MARKER OF PROSTATE CANCER FROM PAGE 6 ered on approximately 1000 men, the Gen- Probe PCA3 test was shown to exhibit a high degree of sensitivity and specificity for prostate cancer. For cancer vs. non-cancer, a specificity of 76% at 50% sensitivity (PCA3 cutoff = 35 copies/copy of PSA mrna), with an area under the ROC curve (AUC) of 0.680, was reported by Fradet s % Biopsy Positive 80% 60% 40% 20% 0% PCA3/PSA x 10-3 : < > 100 # Subjects: Figure 6. Chart showing the higher the PCA3 Score (PCA3/PSAmRNA) (horizontal axis), the greater the likelihood of cancer (vertical axis). From L.S. Marks, et al, 2006 AUA Meeting, Atlanta, GA. Table 2: Operating Characteristics of PCA3 vs. PSA in 225 Men Undergoing Prostate Re-Biopsy PCA3/PSA mrna ratio vs. Serum PSA: Previous negative biopsy group PCA3 Assay Serum PSA Cutoff PCA3/PSA = 35 x ng/ml Sensitivity 58% 83% Specificity 74% 17% *ROC AUC Odds ratio *P = Figure 7. Diagram showing PCA3 specimen collection. The procedure begins with an attentive digital rectal exam (3 sweeps on each side of the prostate). First voided urine is then collected and sent to laboratory for analysis. group. By comparison, serum tpsa specificity was only 22% for the same men. In addition, the quantitative PCA3 score correlated with the probability of positive biopsy in this population: at low PCA3 Scores (< 5) the biopsy positive rate was only 20%, while at PCA3 scores > 100 the risk of positive biopsy was 67%. A suggestion was presented in Schalken s recent data that some correlation with Gleason grade and cancer volume may also be present. In data from USRF, almost no overlap was seen in PCA3 scores from men with cancer and men with only BPH, confirming the specificity of the test. PCA3 RNA is uniformly undetectable in urine from post-radical prostatectomy patients, even following attentive DRE. A particularly important role of the new marker appears to be in men with persistently elevated serum PSA levels, but a negative initial biopsy. In such men, who constitute a large problematic group, the odds ratio for the PCA3 test to predict cancer upon re-biopsy is 3.6, compared to only 1.2 for serum PSA testing 10 (Table 2). PCA3 testing is highly dependent on the cutoff score used to determine a positive or negative test, because sensitivity and specificity vary reciprocally with the score. The higher the cutoff, the greater the specificity and the lower the sensitivity; the lower the cutoff, the greater the sensitivity and the lower the specificity. Thus, although the test is now available commercially, physicians must be cautious in interpreting the lab report, They should know the performance characteristics of the assay before decisions are based on a positive or negative test result. U.S. laboratories currently offering the PCA3 test commercially include Bostwick Laboratories, Richmond, VA ( and AmeriPath Laboratories, Palm Beach Gardens, FL ( PCA3/). The test is not currently approved by the US FDA. The method of specimen collection is shown in Figure 7. PCA3 Score vs. PSA Testing In comparison with serum levels of PSA, the urinary PCA3 score appears to be highly specific for prostate cancer (Figure 8).While serum PSA levels are known to be influenced by volume of BPH tissue, age, inflammation, trauma, and use of 5 alpha- continued on page 8 PCRI INSIGHTS 7

8 PCA3: A GENETIC MARKER OF PROSTATE CANCER FROM PAGE 7 60 PCA3/PSA mrna 10 Serum PSA (ng/ml) PCA#/PSA x ng/ml Prostate vol. (cc): # Subjects: < > < > Figure 9. Charts showing relationship of prostate volume to serum PSA levels (right) and PCA3 score (left).while PSA is directly related to prostate volume, the PCA3 score appears to have no relationship to prostate volume. Thus, prostate volume, one of the primary factors influencing serum PSA levels, is not a confound of the PCA3 score. Improved cancer specificity is a major advantage of PCA3 testing. From L.S. Marks, et al, 2006 AUA Meeting, Atlanta, GA. Figure 8. Diagram showing urinary PCA3 (lower arrow) vs serum PSA (upper arrow). Whereas PSA is a glycoprotein that may enter the bloodstream, PCA3 is a gene that exists in the nuclear material of prostate epithelial cells which may be shed into the urine. Those cells, if cancerous, over-express the gene. That over-expression, which may be many times that found in benign prostate cells, is detected by the assay. Importantly, PCA3 expression is normalized against a background of prostatespecific nuclear material (PSAmRNA), yielding a PCA3 score.the PCA3 score is much more cancer-specific than serum PSA levels, which are confounded by factors such as prostate volume, age, trauma, and certain drugs. reductase inhibitors (finasteride, dutasteride), preliminary data indicate that these factors do not appear to influence PCA3 scores. For example, standard teaching is to draw blood for PSA levels before a DRE, for fear the exam might cause spurious elevations in serum PSA. However, an attentive DRE actually increases the informative rate of PCA3 determinations and is,in fact,recommended.in Figure 9,the effect of prostate volume is shown on both PSA and PCA3 in the same group of adult men. Clearly, PSA is directly related to prostate volume, while PCA3 is not. Unpublished data from USRF indicate that the same is likely to be true for age and use of 5ARI drugs. Thus, with the caveat that data are limited, the urinary PCA3 score appears to offer a great specificity advantage over serum PSA levels in the early diagnosis of prostate cancer. Conclusion and Future Directions The PCA3 gene, a noncoding segment of mrna located on chromosome 9, is 8 PCRI INSIGHTS over-expressed by prostate cancer cells in comparison with all other cells studied. The differential expression is great, permitting detection of the gene in nuclear material from cancer cells shed into urine after an attentive DRE. Thus, urinary PCA3 appears useful as a highly specific marker for prostate cancer. However, while the early data look promising, the PCA3 test must still be regarded as a work in progress, from several perspectives. PCA3 expression is denoted against a background of prostate-specific genetic material, a PCA3 score (i.e. a ratio of PCA3 to PSA mrna), and normative values have only been defined in a preliminary fashion. Factors regulating PCA3 gene expression are not yet clearly defined, but the great confounds of serum PSA levels (prostate volume, age, trauma) appear to affect PCA3 to a much lesser degree than PSA. Additional clinical research trials, now in an organizational phase, should provide further guidelines for widespread application of the urinary PCA3 score. References 1. Magklara A, Scorilas A, Stephan C, Kristiansen GO, Hauptmann S, Jung K and Diamandis EP: Decreased concentrations of prostate-specific antigen and human glandular kallikrein 2 in malignant versus nonmalignant prostatic tissue. Urology. 56: , Thompson IM, Ankerst DP, Chi C, Lucia MS, Goodman PJ, Crowley JJ, Parnes HL and Coltman CA, Jr.: Operating characteristics of prostate-specific antigen in men with an initial PSA level of 3.0 ng/ml or lower. JAMA. 294: 66-70, Stamey TA, Caldwell M, McNeal JE, Nolley R, Hemenez M and Downs J: The prostate specific antigen era in the United States is over for prostate cancer: what happened in the last 20 years? J Urol. 172: , Bussemakers MJ, van Bokhoven A, Verhaegh GW, Smit FP, Karthaus HF, Schalken JA, Debruyne FM, Ru N and Isaacs WB: DD3: a new prostate-specific gene, highly overexpressed in prostate cancer. Cancer Res. 59: , de Kok JB, Verhaegh GW, Roelofs RW, Hessels D, Kiemeney LA, Aalders TW, Swinkels DW and Schalken JA: DD3(PCA3), a very sensitive and specific marker to detect prostate tumors. Cancer Res. 62: , Schalken JA, Hessels D and Verhaegh G: New targets for therapy in prostate cancer: differential display code 3 (DD3(PCA3)), a highly prostate cancer-specific gene. Urology. 62: 34-43, References continued at right

9 GLEASON GRADE MIGRATION: CHANGES IN PC GRADE IN THE CONTEMPORARY ERA FROM PAGE 3 been proposed. Up until recently, pathologists have been somewhat uncertain as to how to deal with the grading of prostate cancers in the face of evolving changes in prostate cancer detection. In late 2005, the International Society of Urologic Pathologists (ISUP) in conjunction with the WHO made a series of recommendations 10 for modification of the Gleason grading system to reflect contemporary knowledge, alleviate uncertainty and promote uniformity in its application. Amongst a broad series of proposals, one recommendation was for pathologists to report all higher tertiary grade components of the tumor as part of the Gleason score. For example, suppose a pathologist observes three patterns of cancer in a single specimen: 60 % Gleason grade 3, 30 % Gleason grade 4 and 10% Gleason grade 5. Historically, this would be reported as Gleason score 3+4=7/10. With the revised system, it would instead be scored as Gleason score 3+5=8/10. Another recommendation was made for reporting of any higher grade cancer, no matter how small quantitatively. Previously, any secondary grade that occupied less than 5% of the specimen would not be reported. Currently, even a small percentage PCA3 References FROM PAGE 8 7. Hessels D, Klein Gunnewiek JM, van Oort I, Karthaus HF, van Leenders GJ, van Balken B, Kiemeney LA, Witjes JA and Schalken JA: DD3(PCA3)-based molecular urine analysis for the diagnosis of prostate cancer. Eur Urol. 44: 8-15; discussion 15-6, Fradet Y, Saad F,Aprikian A, Dessureault J, Elhilali M, Trudel C, Masse B, Piche L and Chypre C: upm3, a new molecular urine test for the detection of prostate cancer. Urology. 64: 311-5; discussion 315-6, Tinzl M, Marberger M, Horvath S and Chypre C: DD3PCA3 RNA analysis in urine--a new perspective for detecting prostate cancer.eur Urol.46: 182-6; discussion 187, Groskopf J, Aubin SM, Deras IL, Blase A, Bodrug S, Clark C, Brentano S, Mathis J, Pham J, Meyer T et al.: APTIMA PCA3 molecular urine test: development of a method to aid in the diagnosis of prostate cancer. Clin Chem. 52: , Marks LS, Fradet Y, Deras IL, Blase A, Mathis J,Aubin SMJ, Cancio AT, Desaulniers M, Ellis WJ, Rittenhouse HG, Groskopf J: Prostate cancer specificity of PCA3 Urinary Gene Test. In Press, Urology, of Gleason 4 or 5 would be incorporated into the scoring system. These two modifications to the Gleason system are expected to further to contribute to Gleason grade inflation in the future. What Does Grade inflation and Changes to the Gleason System Mean for Patients? Patients and physicians must incorporate information from these studies to the care and follow-up of patients with prostate cancer. First, we must be careful how we compare information and clinical studies of contemporary series with older reports. Clinical outcomes (standardized for Gleason grade) may appear somewhat worse in older trials as an artifact of an older application of the Gleason grading system. Conversely, a patient diagnosed with a modern Gleason grade may be expected to do better than the historical controls. Therefore, comparing recent studies to historical or retrospective results may be even more suspect and problematic than previously thought. Second, we should be aware of which interpretation of the Gleason system ( classical or modern ) is used depending on specific uses. Note that most of the widely used clinical outcome prediction tools (such as the Kattan nomograms or the Partin tables) incorporated only the older interpretation of the Gleason system as read by the original pathologists years ago. Therefore, the classical Gleason system read in a way more like the original pathologist should be used if we want to apply these nomograms to individual patients. However, the full description of the Gleason score (and potentially a different number) may still hold useful information. In particular, patients with minor components of high-grade cancer may need more aggressive monitoring or treatment compared with other patients of a similar grade. Further, reevaluation of the original biopsy material (especially by a highly experienced prostate pathologist) may provide new information to guide in patient man- agement. Summary It is clear that an upward drift in the Gleason grades and scores of prostate cancers has been occurring over the past decades. Recent recommendations by the ISUP/WHO will most certainly cause further migration to higher grades and total Gleason scores. This is in turn affecting the apparent clinical outcomes in patient studies, and will most likely continue to do so for the foreseeable future. A greater understanding of this phenomenon is necessary, especially when interpreting comparative outcome data. References 1. Thompson et al. Stage Migration and Grade Migration in Prostate Cancer:Will Rogers Meets Garrison Keillor.J Natl Cancer Inst 2005; 97: Albertsen, PC et al. Prostate Cancer and the Will Rogers Phenomenon.J Natl Cancer Inst 2005; 97: Kondylis, et al. Prostate Cancer Grade Assignments: The Effect of Chronological, Interpretive and Translation Bias. J Urol 2003; 170: Chism et al. The Gleason score shift: Score for and seven years ago.int J Radiat Oncol Bio Phys 2003; 56: Smith et al. Gleason Scores of prostate biopsy and radical prostatectomy specimens over the past 10 years. Cancer 2002; 94: Schellhammer et al. 15-year minimum follow-up of a prostate brachytherapy series: comparing and the past with the present. Urol 2000;56: Stamey TA et al. Biological determinants of cancer progression in men with prostate cancer. JAMA1999;281: Chin-Chen P et al. The prognostic significance of tertiary Gleason patterns of high grade in radical prostatectomy specimens.a proposal to modify the Gleason grading system A J Surg Pathol 2000;24: Epstein et al. Gleason score 2-4 adenocarcinoma of the prostate on needle biopsy. Am J Surg Pathol 2000;24: Epstein et al. The 2005 International Society of Urologic Pathology (ISUP) Consensus Conference on Gleason Grading of Prostatic Carcinoma. Am J Surg Pathol 2005;29: Selected Additional References Feinstein et al.the Will Rogers Phenomenon: Stage migration and new diagnostic techniques as a source of misleading statistics for survival in cancer. New Engl J Med 1985; 312: Pan et al. The prognostic significance of tertiary Gleason patterns of higher grade in radical prostatectomy specimens,am J Surg Pathol 2000;24: Egevard et al.current practice of Gleason grading among genitourinary pathologists. Hum Pathol 2005;36:5-9. PCRI INSIGHTS 9

10 Highlights of the European Association of Urology By Douglas Chinn, MD In April 2006 the European Association of Urology (EAU) held its 21st annual meeting in Paris. This meeting is the largest urological meeting in Europe, and second largest in the world (the American Urologic Association-AUA is number one). There were 11,681 participants, including 9146 delegates. The EAU is based in the Netherlands, and its aim is to promote urology in Europe and worldwide. The EAU does not operate in a vacuum, and there is much interaction with the AUA. However, the EAU operates totally independent of the AUA. Highlights of the Presentations The primary topics of the meeting were prostate cancer,female incontinence and overactive bladder, angiogenesis and renal cell carcinoma, and erectile dysfunction. For prostate cancer, minimally invasive new technology for the treatment of prostate cancer was a major focus of the conference.at the introductory the press conference,professor Pierre Teillac,Medical Director of Saint-Louis Hospital, Paris, France,commented that radical prostatectomy (RP) with an overall 10 year survival rate of 85% is still considered the gold standard by which all other treatments are measured. However, he went on to say, further work is needed to decrease impotency and incontinence.he pointed out that with brachytherapy, the incidence of erectile dysfunction (ED) approaches that of radical after several years, and that the best patients for brachytherapy should be in the low risk group (stage T2a or less, PSA < 10, Gleason Score < 7). Professor Laurent Boccon-Gibod, Secretary General of the EAU Executive Committee, Professor and Chair, Department of Urology, Centre Hospitalo-Universitaire Bichat,Paris,France,presented an overview of radical prostatectomy at the press conference. He explained that clinical data from today s RP procedures continues to demonstrate improved outcome results, and that, over time, side effects can be minimized, but not eliminated. In discussing the risks of incontinence and ED after surgery, he placed them in the proper perspective, saying We 10 PCRI INSIGHTS do not improve upon a man s pretreatment ED or urinary incontinence, we can only make it worse. He explained that any patient, in making a decision for radical prostatectomy, must understand that at best, surgery will have a neutral effect upon continence and ED. And at worst, it can seriously affect his quality of life. The entire panel at this session agreed that currently, spontaneous erections were maintained by only 50-55% of patients after radical prostatectomy, regardless of the type of procedure. Professor Teillac discussed the role of PSA and the oft-cited controversy over the value of PSA screening and its potential for over-diagnosis. He gave a very interesting perspective in which he reminded attendees of the difference between knowledge and action. There is never such a thing as too much knowledge, he asserted, and prostate cancer, screening by PSA and diagnosis by biopsy simply provides valuable knowledge. Hence, over-diagnosis is not the issue since over-diagnosis does not cause over-treatment. Treatment, including watchful waiting, is an action. The real issue, therefore, is the possibility of over-treatment caused by the lack of knowledge that PSA screening and other tests can provide. Of course, once there is knowledge, there will be anxiety, but it is determining what action should be taken with this knowledge that is the real controversial topic. Thus, screening is important, and knowledge trumps lack of knowledge any day. Professor Guy Vallencien Chief of Urology, Institut Mutualiste Monsouris Paris, France, presented a state-of-the-art lecture on Functional Outcomes after Radical Prostatectomy and Brachytherapy. He provided an extensive review of the literature, and explained that much of the confusion of outcome data is due to the non-standardized collection and assessment of the pre- and post-operative information. In this retrospective study literature, not all of the same data was collected or statistically analyzed the same way, he pointed out, nor was this collection discrepancy always defined. Patient assessment surveys for ED and incontinence were also varied or not well defined. This contributes to the varied outcome data results, so that the findings of any such large retrospective study may well be suspect. In fact, he states that the data was like the Tower of Babel, and it is no wonder patients are confused about treatment choices. Consider just the ranges of the data. For RP, the average continence rate at 12 months was 83%, and the meta analysis at two years for average potency, with or without drugs, with nerve-sparing, is 50%. However, the ranges in this retrospective study are huge: with a range of % for continence and a range of % for potency. There was a similar pattern in brachytherapy reports. The meta analysis at three years concluded that the mean continence was 84% and mean potency was 55%, but again,the ranges were huge:55-100% for continence and 11-91% for potency. Aside from the lack of a standardized or consistent data,vallancien also lamented the fact that certain crucial data was almost universally absent. 1. For incontinence, there is very little information about ancillary procedures, including artificial sphincters. 2. There is very little information about urinary symptoms, including urgency and frequency 3. For sexual function, there is no information on ancillary procedures, penile implants, vacuum pump, or penile injection therapy, urethral suppositories or oral agents. Hence, it is very difficult to rationalize the outcome data from study to study and come up with reliable cumulative results. Quality of life data was also addressed, and the most surprising data came from a paper by Saranchuk, Scardino et al (J. Clin Oncol 23:4146, 2005) in which 647 patients, with an average age of 57 at treatment (RP) and stages T1-T3 were evaluated. The parameters evaluated were:

11 HIGHLIGHTS OF EAU CONGRESS FROM PAGE Cancer free (PSA <0.2), 2. Urinary continence 3. Potency As shown below, the quality of life improves slowly and marginally each year.vallancien was surprised at the QOL of only 53% at four years.if studies do not indicate the time after treatment in determining a mean QOL, the results will be at best misleading. 1 yr 2 yrs 3 yrs 4 yrs QOL: 30% 42% 47% 53% Vallancien also reviewed two other papers concerning QOL. The results, which are summarized in Tables 1 and 2, demonstrate that radical prostatectomy has a lower early, QOL, but improves with time, whereas QOL decreases over time after brachytherapy. (It should be noted that the measured parameters for the three QOL studies were not defined at the talk.) Table 1. Quality of Life at 7 Months 1 (lower score is worse) QOL Control Radical Brachytherapy Prostatectomy Urinary function Urinary bother Bowel function Bowel bother Sexual function Sexual bother Brandes et al J. Urol 163:851, 2000 Table 2. Quality of Life at 6.2 Years 2 (lower score is worse) Symptoms Control Radical Conformal Prostatectomy XRT Brachytherapy Urinary Irritation Urinary Incontinence Sexual Dysfunction Bowel symptoms Vitality Miller D., et al, J Clin Oncol 23:2777, 2005 With the undeniable value of welldesigned retrospective studies,i totally agree with Dr. Vallencien s recommendations that clinical studies of local treatments standardize their data collection and reporting with the following: 1. Include pre-treatment assessment of urinary and sexual function 2. Use validated questionnaires at three years: urinary status, sexual function, PSA, and global health of patients, and standardized statistical data 3. Assess urinary status, including all urinary symptoms and any ancillary procedures 4. assess sexual function using a standardized questionnaire, and also including all sexual functions, plus use and dependence upon medical therapy, and ancillary procedures. 5. Stratify evaluation of two groups of patients, those with PSA < 0.2 and those requiring secondary treatment From a patient s perspective, I personally feel that urinary, bowel, and sexual function should be evaluated and reported on patients at 1 month, 3 months, 6 months, 12 months, 5-6 years, and 10 years. I recommend this because each treatment modality can have significant side effects at different time intervals, and they may resolve or get worse with time. For example, early postoperative RP patients often have total urinary incontinence and have to wear diapers constantly for up to 6-12 months, before they regain control, while radiation therapy patients may develop urinary urgency, frequency and incontinence 3-10 years later, and brachytherapy patients may have urinary frequency, urgency and very slow stream for the first year. Patients need to be and should be able to understand what QOL will be like during these time intervals. Manfred Wirth, Professor and Department Head,Urology,Carl Gustav Carus Medical School, Technical University of Dresden, Dresden, Germany, provided an assessment of robotic surgery. He noted that there has been a rapid increase in its use. In just three years, its use has grown by over 300% to 16,000 procedures in the U.S. Professor Wirth provided a literature review, and stated that the consensus of the studies was that robotic-assisted radical prostatectomy (RP) has the following advantages over open surgery: Substantially less postoperative pain Shorter recovery period Reduced risk of blood transfusion Less scarring Lower risk of wound infection This assessment was by no means absolute,however.for example,a study at the Vattikuti Urology Institute in Detroit suggests that robotic-assisted RPs improved cancer control and resulted in a lower incidence of impotence and urinary incontinence whereas another study by Ahlering, at UC Irvine, Irvine, CA found no difference. In fact, the news conference panel concluded that the skill and experience of the surgeon is still the paramount factor. I believe that the take-home message is that robotic surgery represents the latest technology and is here to stay. There appears to be definite improvement in immediate postoperative morbidity, but there is not as yet adequate direct evidence as to which procedure results in superior long-term outcomes. I tend to agree with the conclusion of the panel that favorable outcomes depend less on the technology utilized and more upon who is performing the procedure. The biggest personal surprise of the meeting came from Peter Scardino, Chairman of the Department of Urology, Memorial Sloan Kettering Cancer Center, NY. He actually discussed and promoted focal therapy as a therapeutic treatment in highly selective patients, as an alternative to watchful waiting with delayed intervention (a topic I previously presented in the PAACT Cancer Communications Newsletter, Volume 18, No. 5 December 2002). Dr. Scardino strongly stated his view that traditional treatments may be overkill in cancer with very low malignant potential. In support of this view, he described in detail such factors as the risk of perioperative complications, long-term continued on page 12 PCRI INSIGHTS 11

12 HIGHLIGHTS OF EAU CONGRESS FROM PAGE 11 issues with ED and incontinence for radical surgery, and ED, bowel, and urinary side effects associated with radiotherapy. Dr. Scardino also clearly explained the risks of focal therapy, but surprised almost everyone by stating that he now felt that there were suitable indications for focal therapy, and that long-term careful surveillance is required. He supported the role of selected core biopsies and Endorectal MRI in evaluating potential candidates for focal therapy. Even more intriguing, he singled out the My Personal Assessment use of an experimental technology, Vasculartargeted Photodynamic Therapy as the primary therapy, seemingly indicating that he believes it to be superior to focal cryosurgery. In the process, he ignored the role of highintensity focused ultrasound,despite the body of early HIFU data currently available. (I was particularly bemused by this oversight since I have been utilizing Endorectal MRI and focal cryosurgery since 1993.) Regardless of the technology, I believe this topic represents a radical shift in the By Doug Chinn, MD thought process of treating very low-risk forms of prostate cancer, especially from an eminent proponent of radical prostatectomy. Furthermore, it is encouraging to see new technology being embraced as an alternative to traditional therapies that entail risks that can only make things worse, and a progressive thought process developing to improve patient lives. PCRI nsights As a veteran attendee of the annual AUA conferences, I found the EAU Congress to be refreshingly different. Of course, the EAU meeting was much smaller, but the plenary sessions were in full attendance. The basic difference seemed to be two different philosophies. At the EAU Congress, I sensed more openness and introspective discussion of the options for prostate cancer. For the most part, the speakers would discuss their areas of expertise, but none really claimed superiority. It was more of just stating the pros and cons and presenting new outcome data, (individual or multiple articles) and inviting the listeners to form their own opinions. Rarely did any speakers promote a single individual and his results, so that the presenters gave an impression of more openness, and there was less inclination for the presenters to feel pressured to be the best. There was a real willingness to provide a forum for discussion of new, novel and experimental treatments. This was in direct contrast to many AUA-type presentations that caution: it may not work, there are many complications and it s experimental (so not worth discussing). Rather, experts at the EAU Congress were allowed to present data that was then discussed, and taken for what they were: glimpses into what may be valuable research and treatment in the future. At the EAU Congress, I did not perceive the academic not invented here syn- 12 PCRI INSIGHTS drome that implies that if no specific academic center(s) were involved, the presentation was unlikely to have scientific merit. I heard only one plenary EAU speaker display such an attitude, even with discussing the newer treatment modalities of cryosurgery and HIFU. The meeting itself is more compact, with fewer sessions, but even so there was less conflict of subject schedules, at least for me, who was concentrating on minimally invasive procedures for prostate cancer. At the AUA conference in Atlanta, the topics were spread over several days, but even so the schedules of presentations dealing with similar areas of interest were often in conflict, and attendees had to choose between them as they could not hear both. It is ironic that while cryosurgery is an accepted procedure by the EAU, and HIFU is not, the number of HIFU presentations and posters exceeded those of cryosurgery by at least 10:1. It was refreshing to note, that although the EAU has not formally accepted HIFU,there was an expressed awareness that in the future, HIFU may be the best choice for focal and salvage therapy. Finally, at least for this year, many of my colleagues, distributors, and friends who attended both the EAU and AUA conferences felt that this year, there was more energy and excitement at the EAU, and there were more innovative topics discussed. Editor: Review Board: Design & Production: Charles Bader Duke K. Bahn, MD Stanley A. Brosman, MD Arthur N. Lurvey, MD Mark C. Scholz, MD Diana Garnand Prostate Cancer Research Institute 5777 W. Century Boulevard, Suite 800 Los Angeles, CA Phone (310) Fax (310) Helpline (310) pcri@pcri.org and 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 Services, mycfo, Inc. Mark C. Scholz, MD, PCRI Co-founder Director, Prostate Oncology Specialists The cost of printing and mailing this newsletter is made possible through a generous grant from The Life Extension Foundation P.O. Box , Hollywood, FL The opinions expressed in the by-lined articles are those of the authors and should not be considered opinions of the PCRI. Copyright 2006.

13 Chicago Town Hall Meeting Creates Spirited Discussion On June 17, 2006, six prostate cancer specialists participated in a spirited discussion regarding treatment options for patients with hormone refractory and advanced prostate cancer. The meeting was produced by the PCRI and underwritten by an educational grant from Abbott Oncology. It was held at the Hyatt Regency O Hare and included twentyone patients and six partners from the Chicago area and several diverse locations like: Waleska, GA, Cooperstown, NY and Boise, ID. PCRI Program Director Harry Pinchot moderated the session by directing questions submitted by the attendees to the panel of five medical oncologists and one urologist: Oliver Sartor, MD, Dana-Farber Cancer Institute, Boston, MA Charles Myers, MD,American Institute of Diseases of the Prostate, Free Union,VA Steven Tucker, MD, The Angeles Clinic, Santa Monica, CA Nicholas Vogelzang, MD, Nevada Cancer Institute, Las Vegas, NV Daniel Shevrin, MD,Evanston Northwestern Health Care, Evanston, IL Gerald W Chodak, MD,Midwest Prostate and Urology Health Center, Chicago, IL The questions were grouped under general topics: Second-line Treatments, Chemotherapy, Bone Strengthening, Novel Agents and Quality of Life Issues. The following were among the many comments worth noting: If we could completely eliminate androgen, we could keep more patients from developing hormone refractory prostate cancer (HRPC). Most PC still needs the androgen receptor. In breast cancer, there are ways to fully degrade the estrogen receptor. There does not appear to be a major detriment to the use of intermittent androgen deprivation therapy (in patients who achieve an undetectable PSA nadir). Some patients with a fast PSA doubling time and Gleason 9-10 can be put into remission if Taxotere is started early. For HRPC, first-line therapy should be a clinical trial involving Taxotere plus one of many interesting novel agents. In lung cancer, four cycles of chemotherapy are as effective as more but we don t have comparable data for prostate cancer. With chemotherapy supportive care matters big time. The heart of medical oncology is poison control. Attendees had an opportunity for individual discussions with the panel and PCRI representatives during the continental breakfast, morning break, and luncheon. The meeting drew high marks and many favorable comments including: I am in total AWE to be in the same room with these doctors who I believe are truly Saints in the world of cancer and There was excellent dialog between physicians with markedly different approaches to this disease. The meeting was video taped and portions are available for viewing on our website can also request a copy of a DVD by submitting a request online or calling the PCRI Los Angeles office at Advocates Where are You? In the last issue of PCRI Insights,and in the May issue of UsTOO s Hotsheet,we provided a report on a new advocacy movement. The focus is to raise awareness and to seek treatment options for men with advanced prostate cancer. One of the key tenets of the movement is: Advocates must be recruited and trained in both advocacy and the science of the disease. We requested that those of you interested in supporting this movement, send an with your name, address and phone number to: raiseavoice@pcri.org. As of this writing, we have received only 22 responses. For the 48,000 hormone refractory prostate cancer patients in the United States - can t we do better? Where Are We Now? The organizing committee developed an action plan and is working to finalize a position statement detailing: Current statistics relating to advanced prostate cancer A background of the lack of progress in the treatment for advanced prostate cancer A response to other Citizen s petitions which have been submitted to the FDA An impassioned plea regarding the need for new treatment options for these patients A listing of novel drugs and treatments currently in trials and/or approved for other indications This position statement will be reviewed with all of the prostate cancer organizations to seek a consensus. We will be searching out resources needed to impact change media contacts, experts and sponsors as defined by the position statement. We will be asking advocates to assist with publicity for the position statement and to help in recruiting others to convey the importance of this issue. We intend to meet with key decision-makers at the FDA and NCI to present the views of this group and to demand access to novel therapies for patients who do not have other options. A current status of these activities can be found using the Raise A Voice link at PCRI INSIGHTS 13

14 When it Comes to Cancer: YOU ARE THE CAPTAIN OF THE SHIP by Ric Masten When the urologist said, There is nothing more I can do for you, I m sending you along to an oncologist, I went deaf, dumb and blind with fear. I knew that I had advanced prostate cancer and that it had invaded the bone, but now,in less than a year,the hormone blockade had failed,the pain was back and my PSA was rapidly rising again.worst of all, I had wasted eleven months being an ostrich with my butt in the sky and my brains under ground. After the original diagnosis, the urologist, whom I had found in the yellow pages, told me that Medicare would not cover the expense of chemical castration. So, being a penniless poet, I let him perform a bilateral orchiectomy. In other words, I allowed him to pit my apricots. Now, I take the blame for this unfortunate circumstance as I hadn t yet become a proactive patient. Did I get a second opinion - No. Did I go to a prostate cancer support group - No. If I had, I would have discovered that Medicare would indeed cover the cost of chemical castration. But no use crying over lost gonads and at least I learned first hand that doctors are not infallible. I couldn t get an appointment with the oncologist for three weeks. It was during this time that I turned the poor me attitude around. I went on line and found the Prostate Cancer Research Institute, but the medical jargon baffled me. I saw that the site had a Helpline so I dialed the number and surprise; I got a real live human being. He was a fellow PC patient who talked to me for more than an hour. I have since dubbed him Helpline Harry. Before Harry let me go he said: If you remember anything from our conversation remember this You are the Captain of the Ship! I liked Harry s metaphor and realized that we too often put doctors above ourselves in the chain of command. Now, with my trusty computer, I am more a Captain in search of good Navigators. When the appointment with my new navigator finally arrived, I found him to be to an empathetic young oncologist fresh from the Stanford medical enterprise. 14 PCRI INSIGHTS He gave me more than an hour of his time and, in fact, when my questions and treatment had been discussed, it was I who stood up to go. Dr. John was not a clock watching doctor squeezing patients out in fifteen minute intervals. Now, when Dr. John keeps me waiting (and he often does) I just figure he is doing for someone else what he did for me on that first visit. I once brought some material to him about taking more blood tests than just the PSA. This advice had come from a prostate cancer specialist at PCRI. When I gave this information to Dr. John he said, Ric you have a disease that there is no right way to treat. This doctor has his style and I have mine. Well, I brooded about this till my next appointment. Then I said to Dr. John, You are a general oncologist, right? You treat all kinds of cancers, right? Well, how could you know enough about prostate cancer to stay on the cutting edge of all the cancers and still have time to practice medicine. My testing suggestions come from a PC Specialist, so please do the tests! He did, and we discovered that my prostate cancer had become the very aggressive neuroendocrine disease. If I hadn t been the Captain of the Ship, this turn of events would have been discovered during my autopsy. Chemo and radiation treatment followed immediately and I m still here more than seven years out. Interestingly, if a miracle cure came along I would gladly take it, but I will always cherish my experiences struggling with advanced prostate cancer. Because of this disease I have met wonderful people and learned valuable lessons. Since the moment when Dr. John put his hand on mine saying: When the time comes Ric, and it will come, I promise you a graceful end, I have had more close moments with my loved ones, been more alive, more creative, seen more sunsets, then in the entire 69 years that proceeded that terminal diagnosis. I feel blessed! I only hope that you go away from reading this knowing that you are the CAPTAIN OF THE SHIP! How to Contribute to the 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 or call PCRI for the number. Planned Giving: Naming PCRI in your will or as beneficiary of a life insurance policy. Gifts in Honor and Memorials 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. Planned Giving Opportunities For information on Planned Giving opportunities or how to put PCRI in your will, please contact PCRI at (310) , or by at pcri@pcri.org. 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 5777 W. Century Blvd., Suite 800 Los Angeles, CA Credit card donations can be made at or (310) Prostate Cancer Research Institute is a non-profit corporation, exempt from federal income taxes under section 501(c)(3) of the Internal Revenue Code. It has been classified as an organization that is not a private foundation as defined in section 509(a) of the Code, and qualifies for a maximum charitable contribution by individual donors. 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