Vol. 3 No. 11 & 12	November-December 2004

FEATURE ARTICLES

• The Director's Column
• Next Meeting
• Last Meeting
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• Editor's Notes

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RADIATION THERAPIES COMPARED TO SURGERY WHEN TRYING TO CURE PROSTATE CANCER From an advocates opinion. After attending seminars for years the issue of which therapy is better has been an ongoing debate. If one has confirmed with early detection, low volume, nonsystemic prostate cancer, either therapy of all forms should cure. What do I mean by all forms of therapies? In surgery the most common therapy is a radical retropubic prostatectomy, which simply means opening the abdomen from the navel to the pubic bone. A newer approach used with great success at many teaching hospitals is a laproscopic prostatectomy, which there are only four small incisions used and a camera and a operating tube are used that is less invasive that opening the body cavity with the former mentioned surgery.  Remember surgery provides a pathologist with the specimen for final grading and a conclusion whether or not the cancer was organ confined. Radiation therapies are complex. Choices are radio active seed implants that remain in the prostate.  Also short term brachytherapy with high density radiation where no implants remain in the prostate. Then there are beam therapies such as external beam, 3-D conformal beam, IMRT (intensity modified radiation therapy), neutron beam, proton beam, and to make this even more interesting combinations of the radio therapies such a brachytherapy seed implants combined with a form of beam radiation. And just a little icing on top: many times androgen deprivation therapy (testosterone deprivation) needs to be administered before the treatments begin. Here are the side effects. It most commonly agreed that with surgery all side effects are up front and diminish over time and with radiation there usually are small effects early, but bigger effects develop over time. The big picture, to remember, is radiation can kill PC cells outside the prostate gland. Surgery's intent is to remove PC that is inside the prostate capsule or that is organ confined.  See you at the meeting at the January round table meeting ........... henri plunkett Survey results from our local members We have reduced the mailings to 83 from over 125 members as a result of our mailing to you. Gland Volume There is a objective formula for deriving the prostate gland volume which is derived from the ultrasound prior to biopsy.   It used with the baseline PSA, and the derivatives of the formula account for normal psa leakage into bloodstream verses high level psa leakage from the cancer.  This number then formulates into amount of cancer  probable in your prostate gland  and is measured in cc or millimeters of size. It is really not that complex, and I will e-mail the  formula to you if you ask. The point is a good doctor should do this calculation before recommending therapy, but as you know most don't and they will tell you it is not really necessary since they are experts in prediction without the (objective) tests. We have never had a doctor in Sherman who has used modern color Doppler when using ultrasound to measure your prostate size.  This equipment identifies vascular growth to tumor and easily helps predict early detection, or not.  Hormonal reduction adt (adjutant deprivation therapy) should always be used before radio therapy if 1) prostate volume is very large-- to help reduce target area and to sensitize cells for therapy, 2) if Gleason scores show aggressive mutated cancer such as scores of 8,9 10, and also to give patient time to go slowly and choose a therapy best suited for them. 3) if your doctor even remotely suspects systemic spread of cancer then in hopes testosterone deprivation works to destroy those escaped cells while radio therapy will knock out primary tumor..........and, oh!, there is always more..henri After Surgery-- ALL THERAPIES THAT ATTEMPT TO CURE PROSTATE CANCER HAVE SIDE EFFECTS. THIS ADDRESS IS FOCUSED ON EFFECTS AFTER RADICAL PROSTATECTOMIES OR PROSTATE ABLATION THROUGH SURGERY. After surgery is performed a man is usually cleared from a hospital in a few days. However he usually convalesces in home with a catheter in place for a couple of weeks. Then the catheter is removed and the question of whether a man is able to regain continence or not begins. It appears all men have leakage of urine immediately post removal.  Fortunately men seem to experience non-leakage in about five weeks.  Some men experience leakage reduction in this time period but do not achieve continence. In time these men usually do become mostly continent.  However there is a small percentage who do not and will remain incontinent permanently. Obviously this is a bad situation. What medical procedures are available for this problem? First all men should be aware and perform Kegler exercises, (pretend to shut your urine stream off) and hold and release exercise. Next if all fails your urologist may indicate surgery to either put in an artificial sphincter or discuss a simple penile clamp to suppress urine leakage. Obviously both of these methods are not suitable to everyman. The worst case scenarios of incontinence become wearing pads or diapers that must be changed frequently. Or a surgery that drains the bladder into a unit on the outside of the body which sounds worse than it is as I understand this is actually tolerated better than one might think. OK, OK so none of this is a good thing, remember the worst case scenario happens to less than two percent of patients receiving this therapy. NEXT, erectile functioning. Yes there are always residuals after surgery of less potency for all men. This also varies from man to man. Younger men report regaining most of their erectile function, if nerve sparing techniques during surgery were used. As men's ages go up they seem to report less erectile function returning. Although this is a sexual issue, one need not be embarrassed, but only be honest since this way is how to receive help. After surgery usually the seminal vesicles, the prostate and the vas deferens have been removed. What this means is there will be no more ejaculate during climax.  However, sometimes a very small amount of fluid from the Cowpers gland appears as this is a fluid that protects the acid mantle of the urethra and usually this small gland is not removed during surgery. Dry ejaculation is not necessarily a bad thing, some women report this is a positive for them. Now suppose the ability to sustain an erection after surgery does not return? There is actually a lot of help in this area for men. First there are the drugs that increase capillary blood flow to the penis, such as Viagra, Levetra, and Cialis. If these do not help, usually they are used in conjunction with a vacuum pump. Vacuum pumps work by pulling blood into the penis; then the penis must be clamped to maintain the pressure. Downsides are the preparations while maintaining a air of sexual excitement with the mate.  Yes, for some men this seems to be a problem.  If little of this seems appealing then there is surgery. Surgery can implant an inflatable chamber with a pump placed into the scrotum to create an erection, when desired, and deflate on demand. There are also rigid rods that are implanted and you simply bend the penis into position for usage and then bend back when ready. How well these techniques work, of course, varies again from individual to individual. That is why one must always do his homework in the field of prostate cancer, and its related effects, to pick the best physician available in these fields to recommend and execute the best therapy for you........if you need more info see me or a doctor at our meetings. good luck...........henri plunkett Examples of how a good doctor uses gv or gland volume in objective prediction. From Dr. Strum, Henri's favorite source-Ed. -------- ********* Material posted here is intended for educational purposes only, and must not be considered a substitute for informed medical advice from your own physician. ********** From: Stephen B. Strum MD, FACP Medical Oncologist Specializing in Prostate Cancer To: Joseph M. re: Richard LW ---- Original Message ----- Solid presentation of data. I am encouraged by the continuous evolution of the PC patient and support team. A gland volume of 39 cc should equate with a benign PSA production of roughly 2.5. Since the total PSA is 6.3, this leaves an EXCESS of PSA (assumed to be malignancy related) of 3.8 ng. Assuming for the moment that the Gleason score was VALIDATED by an expert in PC pathology, the PSA leak for such a Gleason score is 4.26. Dividing the EXCESS PSA by this PSA leak gives us a calculation of the PC volume, which in this case would be 3.8/4.26 or 0.89 cc of prostate cancer. ASSUMING these calculations have some basis in reality, we can say: 1. This is low volume PC and should be equated with good chance of OCD (organ confined disease). 2. We would predict that other biologic expressions of tumor volume should confirm this. For example, in LW's case, the DRE revealed no palpable disease. This is consistent with small tumor volume but it is just one manifestation. Secondly, the core percentage was only 1 of 6 cores positive for PC. This is a good finding, again consistent with small volume PC. The core involved represented 40% of the biopsy specimen. This too is good. What we do not have is the free PSA percentage to reflect again the lower aggressivity of the PC process. The higher the free PSA percentage, the less aggressive the PC process. Carter HB, Partin AW, Luderer AA, et al: Percentage of free prostate-specific antigen in sera predicts aggressiveness of prostate cancer a decade before diagnosis. Urology 49:379-84, 1997. OBJECTIVES: To evaluate serial measurements of free and total prostate-specific antigen (PSA) as a predictor of prostate cancer aggressiveness. METHODS: Twenty men diagnosed with adenocarcinoma of the prostate in the pre-PSA era had serum PSA measurements made on multiple stored frozen sera samples available for up to 18 years prior to diagnosis. Subjects were categorized as having aggressive cancer (n = 12) based on the presence of clinical Stage T3, or nodal or bone metastases (N+, M+), or pathologic positive-margin disease, or a Gleason score of 7 or greater; nonaggressive cancer (n = 8) was identified by the absence of these criteria. RESULTS: There was no statistically significant difference in free PSA levels among men with aggressive and nonaggressive prostate cancers from 0 to 15 years before diagnosis. Total PSA levels were significantly different between the groups by 5 years before diagnosis (P = 0.04). At a time when total PSA levels were not different between groups (10 years before diagnosis), there was a statistically significant difference in the percentage of free PSA between aggressive and nonaggressive cancers (P = 0.008). Among 14 men who had sera available for analysis at 10 years before diagnosis, all 8 men with aggressive cancers had a percent free PSA of 0.14 or less; this compares with only 2 of 6 men (33%) with nonaggressive cancer. CONCLUSIONS: These data suggest that the percentage of free PSA in sera is predictive of tumor behavior at a time when total PSA levels provide no information on tumor aggressiveness. Evaluation of the percentage of free serum PSA may be helpful in making the decision between expectant management and treatment for those men who are diagnosed with early prostate cancers by PSA testing. -------------------------------------------------------------------------------- PSA HISTORY 11/18/96 RPCI PSA 2.90 06/10/99 RPCI PSA 4.26 09/15/99 RPCI PSA 4.38 12/15/99 RPCI PSA 3.79 03/13/00 RPCI PSA 4.27 01/12/01 Quest PSA 4.70 07/06/01 Quest PSA 5.60 03/27/02 Quest PSA 4.00 04/02/03 Quest PSA 6.20 10/08/03 Quest PSA 5.20 04/15/04 Quest PSA 6.90 08/02/04 Quest PSA 6.30 FPSA 11% PSADT ­ (4/2/03 Thru 8/2/04 = 4 Readings) 9.67 Years.>> A few points to be made. A healthy prostate should make no more than 1.0 ng/ml of PSA. Patients with BPH will exceed this but their PSA velocity will be less than 0.75ng/ml/year and their PSA doubling times will be usually in excess of 12 years, and often 15 years or greater. Any PSA value of greater than 2.0 should be of concern for a man as regard to what does this level reflect. In LW's case, he has had a serial increase in PSA's that is consi stent with a neoplastic process for some time. His variations in PSA with both the Quest and other PSA assay may be a reflection of lab error, sexual activity (ejaculation) within 48 hours prior to the actual PSA testing or to a level of prostatic inflammation (prostatitis). The low Free PSA percentage attests to a need to treat this gentleman since such low values usually indicate biologically active PC. SUPPLEMENT/VITAMIN REGIMEN Multivitamin, 81 mg aspirin QUESTIONS: 1. Based on my BX and my PSA History, am I a candidate for Watchful Waiting??>> I think you are an excellent candidate for a shot at cure of PC after further evaluation. Given the likelihood that you have had PC for at least 8 years, I would not lean towards a watchful waiting (I prefer the term "Objectified Observation") approach. However, I do not know the context of your medical story. Therefore, my first inclination would NOT be to recommend OO. <<2. Should I have further Imaging done such as (CT Scan, Prostascint Scan, Color Doppler etc.) or additional Blood Markers??>> CT scanning in such a setting is essentially worthless. Your risk of lymph node involvement ASSUMING the Gleason score really is 6, CS is T1c, bPSA is 6.3, core percentage is 17%, is negligible per the Bluestein, Narayan, Partin, Kattan nomograms. Thus any study to assess nodal involvement would be not indicated based on our current knowledge of PC. Your risk area needing further assessement is with ECE(extra-capsular extension). The TRUSP that you had for diagnostic purposes SHOULD have mentioned the integrity of the capsule, the seminal vesicles and any concern for involvement beyond the prostate. Unfortunately, the majority of those doing diagnostic TRUSP with biopsies use the TRUSP as a tool for targetting the biopsies and too many urologists do not even generate a formal report of the TRUSP. See Appendix F in "A Primer on Prostate Cancer, The Empow ered Patient's Guide" by Strum & Pogliano for the different "FORMS" used in PC management and how we are NOT utlilizing tools that are cheap and available to more accurately assess the man with PC. When patients join together and demand that such acts of translational medicine be employed, the status of the man with PC will be more akin to the advances that the AIDS patients have made because they are pro-active. Your life is at stake. And, the squeaky wheel gets the grease. <<3. If not WW, which treatment, surgery, external beam radiation, seeds or combination seeds and EBRT offers me the best chance of long-term survival?>> The major issues that face a man re: PC are: 1. Do I have PC? 2. Is it an indolent form of PC, more aggressive or very aggressive? 3. Where is the PC (stage)? 4. What kind of tumor volume do I have? 5. Do I need to down-volume the tumor with ADT(androgen deprivation therapy) prior to a local or regional therapy to make such a therapy more able to totally eradicate the PC? 6. Do I have any particular aspects of my biologic profile that would alter a local, regional or systemic approach to therapy? In your case, 1 & 2 are answered, in my opinion. You do not have indolent PC and it appears that you do not have very aggressive PC. You do appear to have OCD but you need some enhancements of staging. See my presentation in Canada at http://www.cpcn.org/. Your tumor volume appears to be less than 1 cc. Thus, I would suggest the following: 1. PAP blood test since this should be less than 3.0. Han M, Piantadosi S, Zahurak ML, et al: Serum acid phosphatase level and biochemical recurrence following radical prostatectomy for men with clinically localized prostate cancer. Urology 57:707-11, 2001. OBJECTIVES: Serum acid phosphatase (ACP) was once used as the marker for advanced prostate cancer. However, with the development of assays for prostate-specific antigen (PSA), a more sensitive and specific tumor marker, the use of ACP has diminished. We investigated the prognostic value of preoperative serum ACP in predicting prognosis for men with localized prostate cancer following radical retropubic prostatectomy (RRP). METHODS: Of 2293 men treated from 1982 to 1998, 1681 men had a preoperative ACP measurement using an enzymatic assay. We analyzed the actuarial freedom from biochemical (PSA) progression following RRP according to ACP levels. We used multivariate logistic regression and proportional hazards models to determine the independent prognostic value of ACP level with respect of pathologic stage and biochemical recurrence. RESULTS: ACP was not an independent predictor of organ confinement or lymph node involvement in the multivariate logistic regression models using preoperative variables. However, in the proportional hazards model, ACP was an independent predictor of tumor recurrence following RRP, and there was a statistically significant improvement in biochemical recurrence-free survival for men with lower levels of ACP (P <0.001). Furthermore, the normalized hazard ratios of ACP and PSA for predicting biochemical recurrence were similar. CONCLUSIONS: Stratification of men according to their preoperative ACP levels was predictive of patient outcome after RRP. Proportional hazards modeling using preoperative variables demonstrated that the serum ACP level is an independent predictor of tumor recurrence following RRP. Dattoli M, Wallner K, True L, et al: Prognostic role of serum prostatic acid phosphatase for 103Pd-based radiation for prostatic carcinoma. Int J Radiat Oncol Biol Phys 45:853-6, 1999. Department of Radiology, University Community Hospital, Tampa, FL 33613, USA PURPOSE: To establish the prognostic role of serum enzymatic prostatic acid phosphatase (PAP) in patients treated with palladium (103Pd) and supplement al external beam irradiation (EBRT) for clinically localized, high-risk prostate carcinoma. METHODS AND MATERIALS: One hundred twenty-four consecutive patients with Stage T2a-T3 prostatic carcinoma were treated from 1992 through 1995. Each patient had at least one of the following risk factors for extracapsular disease extension: Stage T2b or greater (100 patients), Gleason score 7-10 (40 patients), pretreatment prostate specific antigen (PSA) >15 ng/ml (32 patients), or elevated serum PAP (25 patients). Patients received 41 Gy conformal EBRT to a limited pelvic field, followed 4 weeks later by a 103Pd boost (prescription dose 80 Gy). Biochemical failure was defined as a PSA greater than 1 ng/ml (normal <4 ng/ml). RESULTS: The overall, actuarial freedom from biochemical failure at 4 years after treatment was 79%. In Cox-proportional hazard multivariate analysis, the strongest predictor of failure was elevated pretreatment acid phosphatase (p = 0.02), follow ed by Gleason score (p = 0.1), and PSA (p = 0.14). CONCLUSION: PAP was the strongest predictor of long-term biochemical failure. It may be a more accurate indicator of micrometastatic disease than PSA, and as such, we suggest that it be reconsidered for general use in radiation-treated patients. Reviewer's Comments: This is an additional report on the value of this biochemical test indicating a higher risk of disease outside the prostate and likely to be outside of the RT port of treatment. This is a companion article to that of Moul et al pointing out a four-fold increase in PSAR post RP when the PAP is 3.0 or higher. 2. Do an endorectal MRI and if possible with spectroscopy but do this after waiting at least 8 weeks from the time of the biopsy since post-biopsy hemorrhage will make interpretation of the study more difficult. 3. If possible, try to make sure that those doing the above study have significant skills and also state of the art equipment. I just returned from hearing a presentation by Dr. Barentsz from the Netherlands where the quality of the endorectal MRI is enhanced significantly by the use of the 3.0 Tesla magnet used in the MRI. Dr. Barentsz is also doing "DYNAMIC" MRI which allows an assessement of the prostatic blood flow. An alternative to the above is color Doppler ultrasound with skilled people like Fred Lee, Duke Bahn and others. THEN, with the above findings in hand, along with issues discussed such as your AUA symptom score and Sex Health Information for Men (SHIM) score, you can decide on the issue of RP (nerve sparing) versus Seed Implant with or without external beam radiation therapy (EBRT) +/- ADT, IMRT alone versus IMRT with or without ADT prior to and during IMRT, cryosurgery, HIFU or primary ADT. <<4. Is Laparoscopic/Robotic Prostatectomy proving superior to conventional Radical Prostatectomy or is it too early to tell?>> IMO, too early to tell. My frame of reference is small regarding outcomes using laparoscopic RP and even less so with robotic RP. The latter is in the purview of docs like Ash Tewari. Since Ash is now in NY, perhaps your group should have him speak. Ashutosh Tewari, MD Director Robotic Prostatectomy and Urologic Oncology Outcomes Weill Medical College of Cornell University New York Presbyterian Hospital Brady Urologic Health Center 525 East 68th Street Starr 900 New York, NY 10021 Phone: 212 746-5643 Fax: 212 746 8396 ashTewari @ med.cornell.edu http://www.theehealth.com/robotics/ <<5. Can you identify the centers of excellence where LRP is being performed?>> No. Not enough experience directly or even indirectly on my part. <<6. Please indicate your recommendation for radiation protocol in my case: External Beam, Brachytherapy or both?? If External Beam Plan- IMRT or 3D Conformal??>> I would want additional inputs first re: confirmation of sense of tumor volume and location. If studies confirmed a low tumor volume, then consideration for seed implant alone might be part of my recommendation. I favor IMRT over 3D-CRT but there are still some radoncs that use 3DCRT very well. In either case, I also lean towards the use of ADT3 for purposes of reducing tumor volume and enhancing RT outcomes. I also use the ADT3 to not only decrease the volume but as a prognosticator for RT outcomes. Zelefsky MJ, Lyass O, Fuks Z, Wolfe T, Burman C, et al: Predictors of improved outcome for patients with localized prostate cancer treated with neoadjuvant androgen ablation therapy and three-dimensional conformal radiotherapy. J Clin Oncol 16:3380-3385, 1998. Purpose. - To identify prognostic variables that predict for improved biochemical and local control outcome in patients with localized pro static cancer treated with neoadjuvant androgen deprivation (NAAD) and three- dimensional conformal radiotherapy (3D-CRT). Materials and Methods: Between 1969 and 1995, 213 patients with localized prostate cancer were treated with a 3-month course of NAAD that consisted of leuprolide acetate and flutamide before 3D-CRT. The purpose of NAAD In these patients was to reduce the preradiotherapy target volume so as to decrease the dose delivered to adjacent normal tissues and thereby minimize the risk of morbidity from high-dose radiotherapy. The median pretreatment prostate-specific antigen (PSA) level was 13.3 ng/mL (range, 1 to 360 ng/ml.). The median 30-CRT dose was 73.6 Gy (range, 64.8 to 81 Gy), and the median follow-up time was 3 years (range, 1 to 7 years). Results: The significant predictors for improved outcome as Identified In a multivariate analysis included pretreatment PSA level < or equal to 10.0 ng/mL (P < .001), NAAD-induced preradiotherapy PSA nadir less than or = 0.5 ng/mL (P < .00 1), and clinical stage less than or equal to T2c (P < .04). The 5-year PSA relapse-free survival rates were 93%, 60%, and 40% for patients with pretreatment PSA levels less than or = 10 ng/ml, 10 to 20 ng/ml, and greater than 20 ng/mL, respectively (P < .001). Patients with preradiotherapy nadir levels less than or = 0.5 ng/mL after 3 months of NAAD experienced a 5-year PSA relapse-free survival rate of 74%, as compared with 40% for patients with higher nadir levels (P < .001). The Incidence of a positive biopsy among 34 patients pretreated with androgen ablation was 12%, as compared with 39% for 117 patients treated with 3D-CRT alone who underwent a biopsy (P < .00 1). Conclusion: for patients treated with NAAD and high dose 3D-CRT, pretreatment PSA, preradiotherapy PSA nadir response, and clinical stage are Important predictors of biochemical outcome, Patients with NAAD-induced PSA nadir levels greater th an 0.5 ng/mL before radiotherapy are more likely to develop biochemical failure and may benefit from more aggressive therapies. Prognostic Finding 5-year Relapse Free Survival PSA less than or = 10 93% PSA >10 less than or =20 60% PSA > 20 40% PSA nadir less than or =0.5 after 3m* 74% PSA nadir >0.5 after 3m* 40% * after 3 months of neoadjuvant androgen deprivation with Flutamide 250 mg every 8 hours + Lupron 7.5 mg i.m. monthly. I would interpret this to be the PSA value after a full 3 months of ADT = the PSA taken just prior to starting the 4th injection of Lupron. 81 Gy if done by a radiation oncologist that would be considered an artist. <<7. What would be the major side effects of the treatment you recommend??>> You should read the in-depth portions of the PRIMER ( "A Primer on Prostate Cancer, The Empowered Patient's Guide") that deals with these issues. You have to understand the limitations of time and typing involved here. <<8. What would be the success rate (5-10 years PCa free) of the treatment that you recommend??>> Most studies still have PSA relapse free interval data at 5 years. A few using RT modalities have longer follow up. The Primer has some tables of outcomes relating to RT and cryosurgery at 5 years and beyond. I suggest that you and your group be proficient in your understanding of PC and use the PRIMER as a guide to topic discussions in your meeting. This book reflects decades of experience and extensively reports from the medical literature as well. Good luck. Stephen B. Strum MD, FACP Medical Oncologist Specia lizing in Prostate Cancer =-=-=-=-=-=-= Prostate Cancer Education and Support -- visit the Us TOO website: http://www.ustoo.org/ =-=-=-=-=-=-= Prostate Cancer News You Can Use -- recent articles: TRIAL TO ASSESS IF ZYFLAMEND PREVENTS PROSTATE CANCER DNA VACCINE ELICITS IMMUNE RESPONSE IN PATIENTS WITH PROSTATE CANCER http://www.ustoo.org/screamoutput/news_page_w_sub.htm =-=-=-=-=-=-= Visit the Prostate Events Calendar at http://www.prostatepointers.org/calendar/index.phtml Jerry Bylander, Editor