Prostate Cancer Treatment Decision Information Background

Transcription

1 Prostate Cancer Treatment Decision Information Background A group of Radiotherapy Clinics of Georgia (RCOG) prostate cancer (PCa) patients developed this web site, in part, based on a slide presentation generated by a patient treated in Numerous updates have been made over the past seven years with the most recent early in Our goal was to make the treatment decision process easier for newly diagnosed patients by comparing average 10 year PCa disease free results and serious side effect results. Treatments with insufficient data and those not approved for use in the United States were not compared. PCa patients often use medical journals to help make their treatment decision so we simply grouped key data on a level playing field to support a better understanding of the primary alternatives. The medical community publishes 10 year PCa treatment results based on either the American Society for Therapeutic Radiation and Oncology (ASTRO) measure, the Nadir+2 (Phoenix) measure or the most conservative 0.2 ng/ml and below measure. Unfortunately, these measurements shouldn t be directly compared, which means that many patients are using inflated data to make their treatment comparison decision. A 2002 study by Johns Hopkins that compared average 10 and 15 year disease free ASTRO measurements with 0.2 ng/ml measurements found that the ASTRO measurements inflated disease free results by +17% and +32%. The Nadir+2 measure, which replaced the ASTRO measure a number of years ago has also been documented to inflate disease free results in a similar manner as the ASTRO measure. A different source of comparison error is that on average some centers treat more serious PCa patients than others. This results in a slightly lower average disease free result for those centers. We have also compensated for this more subtle form of measurement bias using a PSA group distribution normalization approach. Since adjustments were made to published PCa treatment results this web site necessarily represents the opinion of the authors, although traceability to the published data is maintained for the reader. Disclaimer: The information presented in this web site should not be considered to be medical advice. It contains a compilation of facts and opinions that were developed and updated over time by various PCa patients. This website has no formal or financial relationship to RCOG. Mail Us 1

2 PROSTATE CANCER TREATMENT COMPARISONS (Updated January 1, 2013) Introduction Sixty one Prostate Cancer (PCa) medical journal publications were evaluated to compare average 10 year all-risk disease free rates and serious urinary, rectal and sexual side effect rates. The goal of this paper is to present those comparisons in a way that helps reduce uncertainty many PCa patients have while making their treatment decision. Most radiation based treatments were measured using the American Society for Therapeutic Radiation and Oncology (ASTRO) criteria and in more recent years the Nadir+2 criteria. ASTRO treatment failure is determined when a man s Prostate Specific Antigen (PSA) increases during three consecutive tests after reaching its lowest point (Nadir). Nadir+2 treatment failure is determined when a man s PSA increases 2.0 ng/ml after reaching Nadir. The majority of men that select Prostatectomy, or one center in Georgia that performs Seeds before (>) IMRT treatment, are considered to have failed treatment if their PSA never drops below 0.2 ng/ml or it later rises above 0.2 ng/ml. Fortunately, two of the medical journals reviewed directly compared ASTRO and Nadir+2 results with 0.2 ng/ml results for the same patient groups. Those results indicated ASTRO and Nadir+2 average 10 year treatment success rates were 17% and 12% higher than the 0.2 ng/ml rates. Directly comparing ASTRO, Nadir+2 and 0.2 ng/ml results is very misleading so adjustments were made to present the results on a more level playing field. In addition, men that discovered their PCa early often select prostatectomy or seed only treatment which indirectly bias those treatment results by up to +7%. However, by comparing treatment ratios of early, intermediate and late detection patients it is possible to estimate treatment selection bias for all treatments. Details of how measurement and treatment selection bias were calculated are shown later. A comparison of average 10 year all risk PCa Disease Free (DF), Group Bias (GB), adjusted DF (adf) and Treatment Failure (TF) rates are presented in Chart A. Chart A. Average 10 Year All Risk PCa Treatment Failure Rates Rank Treatment ASTRO 0.2 ng/ml DF GBin adfin TFin 1 - Seeds>IMRT -n 83% 83%i x %i 14% 2 - Prostatectomy -n 79% 79%i x %ii 21% 3 - IMRT>Seeds 81% -n 69% x % 26% 4 - HDR>EBRT 79% -n 68% x % 29% 5 - External Beam 76% -n 68% x % 30% 6 - Proton Beam 73% -n 62% x % 34% 7 - Seeds Only 73% -n 62% x % 38% 8 - Cryosurgery 69% -n 59% x % 39% 2

3 Chart B provides average 10 year very early detection (ved) PCa treatment estimation results. A Seeds before IMRT (seeds>imrt) Radiotherapy Clinics of Georgia (RCOG) assessment of their average 10 year ved patient treatment failure rate was 3% for patients treated since Dividing 3% by 14%, the average all risk Seeds>IMRT value for RCOG treatment failure equals Then, if you multiply times all of the other TF rates in Chart B you get the estimated ved TF (vtf) rates shown below. Chart B. Average Estimated PCa 10 Year vtf Rates Rank Treatment ASTRO 0.2 ng/ml DF adfi TFin vtfin 1 - Seeds>IMRT -n 83% 83%i 86%i 14% 3% 2 - Prostatectomy -n 79% 79%ii 79%i 21% 5% 3 - IMRT>Seeds 81% -n 69% 74% 26% 6% 4 - HDR>EBRT 79% -n 68% 71% 29% 6% 5 - External Beam 76% -n 68% 70% 30% 6% 6 - Proton Beam 73% -n 62% 66% 34% 7% 7 - Seeds Only 73% -n 62% 62% 38% 8% 8 - Cryosurgery 69% -n 59% 61% 39% 8% Serious urinary, rectal and sexual PCa treatment side effects are then combined with the treatment failure data presented in the first two charts. This was done to provide an example of how serious side effect rate data can be used to support a more informed treatment decision. Patients that are not concerned about sexual side effects or those that would simply like to use the data differently should just add in the serious side effect values that likely apply to them. Men with early detection PCa and those with serious health problems or that are much older than the average PCa patient need to be aware of the potential life changing effects that can be associated with serious PCa treatment side effects. Chart C combines average treatment failure and serious side effect rates for all risk patients; while Chart D provides the same information for men with ved PCa. Chart C. Average 10 Year PCa Treatment Failure & Serious Side Effect Values Rank Treatment DF GBin adfi TFin Urinary Rectal Sexual Total 1 - Seeds>IMRT 83%i x %i 14% 1% 0% 20% n35u 2 - Seeds Only 62%ii x %i 38% 3% 0% 18% n59u 3 - Prostatectomy 79% x % 21% 8% 0% 33% n62u 4 - Proton Beam 62% x % 34% 1% 1% 30% n66u I5 - External Beam 68% x % 30% 1% 0% 37% N68u I6 - IMRT>Seeds 69% x % 26% 1% 0% 45% N72u 7 - HDR>EBRT 68% x % 29% 5% 1% 39% n74u 8 - Cryosurgery 59% x % 39% 5% 0% 75% n119u 3

4 Chart. D Average Estimated PCa 10 Year vtf & Serious Side Effect Values Rank Treatment DF adfi TFin vtfin Urinary Rectal Sexual Total 1 - Seeds>IMRT 83%i 86%i 14% 3% 1% 0% 20% N24u 2 - Seeds Only 62%ii 62%i 38% 8% 3% 0% 18% N29u 3 - Proton Beam 62% 66% 34% 7% 1% 1% 30% N39u 4 - External Beam 68% 70% 30% 6% 1% 0% 37% N44u 5 Prostatectomy 79% 79% 21% 4% 8% 0% 33% N45u 6 - HDR>EBRT 68% 71% 29% 6% 5% 1% 39% N51u I7 - IMRT>Seeds 69% 74% 26% 6% 1% 0% 45% N52u 8 - Cryosurgery 59% 61% 39% 8% 5% 0% 75% N88u The ratio between the 1 st and 2 nd ranked treatments in these four charts, vary from 1.2 to 1.7; while the ratio between the 1 st and 8 th ranked treatments vary from 2.7 to 3.7, so treatment choice can have a significant impact on outcome. All but high risk PCa patients may want to first identify treatments with the lowest side effects and then make their treatment decision based on a subset of those treatments. Patients with very early detection PCa may want to consider postponing their treatment by using Active Surveillance procedures - which has the immediate advantage of zero treatment side effects. However, if their PSA doubling time becomes an issue they would then need to select a preferred PCa treatment approach. Another important consideration is that side effects usually occur earlier while treatment failure often takes years to show up. Not all treatment centers/doctors that perform the same treatment achieve the same result so once a patient has selected his preferred treatment he then needs to find the best treatment center/doctor that performs that treatment. A starting point can be to read applicable treatment comparisons in the following section to get an idea of which references report a better result for a specific treatment type. The patient then needs to search the internet and other information sources to compare candidate centers/doctors based on more recent published data. By the way, it is highly unlikely that the doctor that performed your biopsy (or one of his associates) is the most qualified doctor to provide your treatment. Finally, nearly all PCa doctors have learned how to have a great bedside manner but only a few are truly the very best. By comparing best of the best medical journal PCa treatment results, which was the approach taken in this paper, recently diagnosed patients as well as those who just want to learn more about the effectiveness of long term PCa treatments should be able to use this paper to identify better long term PCa treatment results and treatment centers. It should also help newly diagnosed PCa patients compare treatment side effects, either separately or together, with average 10 year disease free rates. Finally, it should help low risk patients make a more informed choice between Active Surveillance and selecting a treatment with reduced serious side effect rates. It should be noted that some medical 4

5 journal data less than 10 years old was used in this report if the treatment procedure had actually been performed for at least 10 years. The first set of publications used in this comparison consisted of 27 PCa medical journal reports that were identified and reviewed by a group of six Radiotherapy Clinics of Georgia (RCOG) patients. The second set was provided by Mr. Gene Gardner of the Cincinnati Chapter of Us TOO International. They consist of 34 medical journal reports that were evaluated by a Cincinnati doctor specializing in PCa treatment. Treatment Comparisons Eight different types of PCa treatment were compared. However, to do this with the least amount of complexity required two "adjustments". For those not interested in reading the next dozen pages about individual PCa treatment comparisons, they can skip to the middle of the paper and see a listing of the best reported treatment results by treatment type, or simply just view charts A through D and then just review specific treatment comparisons of interest. References that were used to report the best and most credible results are highlighted in bold at the end of this paper. Some of those references also include treatment center information to make it easier for newly diagnosed patients to begin the process of locating the best PCa Center of Excellence treatment centers. The first simplifying adjustment was to identify the single best treatment result for each treatment type based on overall average 10 year disease free rates and the lowest reported serious urinary, rectal and sexual side effect rates. This means that only the highest credible all risk 10 year disease free rate (or conversely the lowest treatment failure rate) and the lowest serious side effect rates are identified for each treatment type. It should be noted that the best disease free and serious side effect results for a single treatment type are not always be identified in the same report. As a result, newly diagnosed PCa patients need to check recently published average 10 year disease free rates and serious side effect failure rates for each treatment center they consider. Centers that reference disease free rates from other centers or average National rates should be ignored. The second simplifying adjustment was to compare average 10 year PCa treatment results by only using the 0.2 ng/ml and below disease free criteria, although the published disease free measure was also listed for traceability. The Nadir+2 measure was developed about seven years ago to replace the ASTRO measure by a group of radiologists after it was acknowledged to have serious long term measurement accuracy problems. Fortunately, a 2002 Johns Hopkins medical journal report (Reference #1) provided a credible way to translate ASTRO average 10 year results to 0.2 ng/ml results. The Nadir+2 measure also results in an inflated 10 year disease free value when compared to the 0.2 ng/ml measure, as described in Reference #2. Treatment results compared in this paper are based on published average 10 year (all risk) disease free data. Relatively small differences to that rule, such as excluding a few patients with PSA levels above 50 ng/ml, or a few patients with T3+ staging, appear to be a fairly common variation to the all risk level approach. Average 10 year disease free 5

6 results for low or intermediate risk patients, which are sometimes highlighted in PCa treatment reports because of their good results, should not be compared with average all risk treatment results. Johns Hopkins documented an average 10 year disease free ASTRO measurement overstatement of the 0.2 ng/ml measurement by +17% and the 15 year ASTRO measurement by +32% for the same group of 2,691 patients (Reference #1). It's easy to identify the reason for that difference when the ASTRO disease free rate remained flat at 90% from the 5th year out to the 15th year; while the 0.2 ng/ml rate dropped from 85% at 5 years, to 81% at 7 years, to 77% at 10 years and finally to 68% at 15 years - where each of those lower rates were documented by patient treatment failures that never showed up in the inflated ASTRO data. What was attempted in this paper was to better "align" the different disease free rate definitions by converting ASTRO average 10 year rates to the 0.2 ng/ml rate based on the Johns Hopkins (ASTRO/1.17) measurement ratio. However, less effective treatments and treatment results for patient groups more difficult to treat could likely result in higher (ASTRO/0.2 ng/ml) ratios than documented by Johns Hopkins, although it is currently the only credible peer reviewed ratio that can be used. For example, Reference #2 listed 10 year ASTRO, Nadir+2 and 0.5 ng/ml disease free results of 73%, 65% and 38%. This means the ASTRO and Nadir+2 measures inflated an even easier to satisfy 0.5 ng/ml measure not by +17% but rather 73%/38% = 1.92 or +92% (ASTRO) and 65%/38% = 1.71 or +71% (Nadir+2); but since they didn't compare their results with 0.2 ng/ml those higher ratios were not used. This situation which has existed for a long time needs to be resolved by the medical community or, if necessary, by the US government by requiring all PCa treatment centers to report their average 10 year (all risk, low risk, intermediate risk and high risk) disease free results using the 0.2 ng/ml measure; and if they want, their previous measure for comparison with earlier reports. Results mentioned in Reference #2 can be used to estimate a first approximation Nadir+2 to 0.2 ng/ml adjustment of 17%/92% to X/71% where X = 12%. Therefore, Nadir+2 results are considered to be inflated by 12% over 0.2 ng/ml results (i.e., Nadir+2/1.12 = 0.2 ng/ml rates). It was decided to number the RCOG patient identified references from #1-#27 and the references provided by the Cincinnati Us TOO organization from g1-g39 (although only 34 were actually compared due to some of them being relatively old). This was done so those reviewing the report could see how the two sets of references contributed to the combined result. Both sets of references are listed separately at the end of this paper. The next step required that all references be grouped under the eight major PCa treatment types and then sequentially compared based on the four applicable comparison criteria. Seeds before External Radiation (Seeds>IMRT or Seeds>EBRT) References for evaluating average 10 year disease free results for Seeds before External Radiation treatment are #5, g10 and g28. However, Reference g10 (2000) was not used as the more recent Reference #5 (2004) publication, by the same treatment center, was compared instead. Reference #5 ( Seeds>IMRT) describes treatment where 1,469 sequential patients with T1T2NxM0 PCa were implanted with I-125 radioactive seeds followed 3 weeks later with six to seven weeks of 5 day per week IMRT treatment. The 6

7 published average 10 year disease free rate for all T1T2NxM0 patients was 83% (0.2 ng/ml); although the 10 year average disease free rate for men 70 and below was reported to be 85%. The results for each age group has increased by 3% since then, according to current non peer reviewed information; however, the 2004 average 83% medical journal published result was used in this paper for comparison purposes. Reference g28 ( Seeds before External Beam Radiation Therapy (EBRT)) describes a PCa treatment where 212 patients with a Gleason score of 2-5 were first treated with I-125 seed implants and patients with higher Gleason levels were first treated with Pd-103 implants. The Seeds>EBRT patients were then treated with EBRT four to six weeks after the seed implants. The 5 year disease free rate for the 212 patients was 91% (ASTRO). Converting that value to an estimated 10 year result equals 91%x0.9 = 82% (ASTRO) and 82%/1.17 = 70% (0.2 ng/ml). So according to Reference #5 the highest reported average 10 year 0.2 ng/ml Seeds>IMRT disease free rate is 83%. References for evaluating serious urinary problems for Seeds before External Radiation treatment are #5, g28 and g29. Reference #5 (2004 Seeds>IMRT) identified that out of 1,469 sequential T1T2NxM0 patients 3.7% were incontinent with about half resulting from men with a Transurethral Resection of the Prostate (TURP). Non TURP patients resulted in a 2% incontinence rate. Based on 2010 Seeds>IMRT data, which is only mentioned to support the following g29 Seeds>IMRT incontinence result, RCOG patients treated following a major treatment improvement in 1992 experienced an incontinence rate that rounded down to 0% (non TURP) and up to 1% (when including TURP patients). Reference g28 ( Seeds>EBRT) identified that out of 212 patients 1.5% experienced urinary retention, 2.8% experienced incontinence and 0.5% urethral stricture for a total serious urinary side effect rate of 4.8%. Reference g29 ( Seeds>IMRT) identified that out of 120 patients 10% experienced Grade 2 urinary side effects and 1% experienced Grade 3 urinary side effects after receiving I-125 implants followed 2 months later by IMRT. So according to Reference #g29 the lowest reported Seeds>EBRT serious urinary side effect rate is 1%. References for evaluating serious rectal side effects for Seeds before External Radiation treatment are #5, g28 and g29. Reference #5 ( Seeds>IMRT) identified that out of 1,469 sequential T1T2NxM0 patients, rectal cauterization was required in 15 (1%) of the patients to correct rectal bleeding and a rectoprostatic fistula developed in 3 (0.2%) of the patients that were repaired. Although not compared in this paper, subsequent improvements to the RCOG treatment procedure resulted in no additional fistula in over 5,000 patients since 2003 resulting in a current average serious rectal side effect rate average of 0%, which agrees with Reference g29. Reference g28 ( Seeds>EBRT) identified proctitis in 47 out of 212 patients (21.4%), fistula in 5 patients (2.4%), rectal wall breakdown in 1 patient (0.5%) and 6 patients (2.8%) required a colostomy and urinary diversion. So at a minimum, 2.4% + 0.5% + 2.8% = 5.7% or 12 out of 212 patients experienced serious rectal side effect rates. Reference g29 ( Seeds>IMRT) identified that out of 120 patients the incidence of Grade 2 rectal side effects was 1% and there were no incidents of higher grade rectal side effects, so serious rectal side effects were 0%. This reference also stated adherence to dose constraints with combination real time brachytherapy using real-time intra operative planning and IMRT is associated with 7

8 a very low incidence of acute and late toxicity. So according to Reference g29 the lowest reported Seeds>IMRT serious rectal side effect rate is 0%. References for evaluating serious sexual problems for Seeds before External Radiation treatment are #6 and g28. Reference #6 (2001- Seeds>IMRT) was briefed at a PCa conference and described RCOG treatment of 1,480 consecutive men (including 1307 men that were 70 or younger for more direct comparison with RP) with either normal erection or mild erectile dysfunction (ED), according to the International Index of Erectile Function-5 (IIEF-5). The probability of preserving sexual function was calculated by the Kaplan-Meier method which resulted in 3 year potency levels of: 93% (7% ED) for 97 men that were 50 and below at the time of their implant; 83% (17% ED) for 204 men between 51 and 55; 81% (19% ED) for 317 men between 56 and 60; 73% (27% ED) for 361 men between 61 and 65; 68% (32% ED) for 328 men between 66 and 70. The average 3 year ED rate for all potent RCOG patients 70 and below was (7%x97+17%x204+19%x317+27%x361+32%x328)/1307 = 23.3%. Reference g28 ( Seeds>EBRT) identified an ED rate of 38% for 100 patients out of 212 patients that were potent prior to treatment. So according to Reference #6 the lowest reported (3 year) ED rate for Seeds>IMRT for men 70 and below is 23%. Seeds Only (Brachytherapy) References for evaluating average 10 year disease free results for Seeds Only treatment are #2, g6, g8 and g9. Reference #2 ( Seeds Only) identified an average 10 year (2,693 patient) disease free rate of 73% (ASTRO) and 62% (0.2 ng/ml) - as measured from a chart in the report. A review of Reference g6 ( Seeds Only) identified a 10 year low risk only disease free rate of 87% (ASTRO) for 125 (I-125) patients; however, since the report didn't present average all risk disease free results it was not used. A review of Reference g8 (2005) identified a 10 year disease free rate of 78% (ASTRO) for 279 patients where 215 patients received I-125 only treatment and 64 received treatment consisting of I-125 seeds followed by 6 months of hormone therapy; although it was also stated that 240 patients received Seed Only therapy and 66 patients received combination therapy. Either way, the data was not used since results for the two treatments were merged. Reference g9 ( Seeds Only) identified I year low and intermediate risk patient disease free rates of 96% and 89% (ASTRO). Since high risk patients were not included and the time period was only 5 years this reference was also not used. So based on Reference #2 the highest reported average Seeds Only 10 year disease free rate was 73% (ASTRO) and 62% (0.2 ng/ml). References for evaluating serious urinary problems for Seeds Only treatment are g23, g24, g25 and g27. Reference g23 (1999) was a five year comparison study of 145 I-125 Seeds Only patients and 137 3DCRT patients that for the Seeds Only patients identified Grade 2 urinary toxicity in 45 patients (31%) with a duration of 12 to 70 months; and Grade 3 acute urinary retention in 5 patients (3%) that required catheterization. Reference g24 ( Seeds Only), a two year study of 87 low risk I-125 patients identified Grade 2 and 3 level urinary toxicity levels of 32% and 6% (there were no Grade 4 or 5 toxicity levels). Five patients (6%) developed acute urinary retention within 8

9 12 hours of the procedure requiring the placement of a catheter. Two of these patients (2%) experienced persistent retention requiring suprapubic catheter placement. However, this Reference was not used because it only involved low risk patients as it is likely that more than 2% of all risk patients would have experienced acute urinary retention. Reference g25 ( Seeds Only) indicated acute urinary retention associated with I- 125 interstitial implantation of the prostate gland was generally most significant one month after implantation but improved over the first two years to eventually drop back to pre implant baseline levels. Reference g27 ( Seeds Only) indicated that 8% of 92 patients with acute urinary retention required a TURP to resolve their retention problem. So based on Reference g23 the lowest reported Seeds Only acute urinary retention side effect rate is 3%. References for evaluating serious rectal problems for Seeds Only treatment are g9, g23, g27 and g32. Reference g9 ( Seeds Only) indicated 1% of 367 patients experienced Grade 3 late rectal toxicity. Reference g23 (1999) indicated none of the 145 patients that received I-125 seeds developed grade 3 or higher rectal toxicity resulting in a 0% serious rectal side effect rate. Reference g27 ( Seeds Only) indicated 5 patients (5%) out of 92 developed radiation-induced rectal ulceration's and 3 patients (3%) required a colonoscopy for prostatic-rectal fistula. Reference g32 ( Seeds Only) indicated that 17% of 109 patients developed persistent, bright red rectal bleeding for 1 to 28 months following I-125 treatment; 9 patients (8%) were treated with steroid enemas; and Laser coagulation treatment was given to 3 patients (3%). So according to Reference g23 the lowest reported Seeds Only serious rectal side effect rate is 0%. References for evaluating serious sexual problems for Seeds Only treatment are g7, g23, g27 and g38. Reference g7 ( Seeds Only) indicated that the potency rate of Permanent Prostate Brachytherapy patients for 1,166 patients was 76% at 5 years with an ED rate of 24%. Reference g23 (1999) indicated that the ED rate of 132 men who were potent before brachytherapy treatment was 21% at 2 years and 53% at 5 years; however, the large change from 2 to 5 years does not appear credible. Reference g27 ( Seeds Only) indicated that 56 of a total of 92 patients were potent prior to treatment and 48 (86%) remained potent at 3 years, for an ED rate of 14%; however, they also reported a 4 year disease free rate of 63% based on a treatment failure "cut point" of 1.0 ng/ml (five times higher than the 0.2 ng/ml measure). Had the 0.2 ng/ml measurement reference been used this would have resulted in a much lower 10 year disease free rate, so it's possible the radiation intensity may have been below normal (which in turn could have resulted in an artificially lower ED rate). Reference g38 ( Seeds Only) was a study of 60 pre-treatment potent men, with 30 not potent after treatment and 30 that were potent after treatment - an interesting study but it didn't provide applicable comparison data. So according to Reference g7 the lowest reported average 5 year ED rate for Seeds Only treatment is 24%. Radical Prostatectomy (RP) References for evaluating average 10 year disease free results for RP treatment are #1, #7, #8, #9, #10, #11, g1, g2 and g3 which cover the full range of Open, Laparoscopic and 9

10 Robotic procedures. Reference #1 ( RP) identified a 77% (0.2 ng/ml) average 10 year disease free rate for 2,691 patients. Reference #7 ( RP) identified a 74% (0.2 ng/ml) average 10 year disease free rate for 2,370 patients. Reference #8 ( RP) identified a 76% average 9 year disease free rate for 1,657 patients (76%x0.95 approximates a 72% 10 year 0.2 ng/ml disease free rate). Reference #9 ( RP) identified a 79% (0.2 ng/ml) average 10 year disease free rate for 1,881 patients. Reference #10 ( RP) identified a 79% (0.2 ng/ml) average 5 year disease free rate for 1,564 Laparoscopic patients (79%x0.9 approximates a 71% 10 year disease free rate). Reference #11 ( RP) identified a 84% average 5 year disease free rate for 2,766 Robotic patients (84%x0.9 approximates a 76% 10 year 0.2 ng/ml disease free rate). Open, Laparoscopic and Robotic RP 10 year disease free rates ranged from 68% to 79%. Reference g1 ( RP) identified a 77% (0.2 ng/ml) average 10 year disease free rate for 1,746 patients. Reference g2 ( RP) identified a 72% (0.2 ng/ml) average 10 year disease free rate for 2,091 patients. Reference g3 ( RP) identified a 68% (0.2 ng/ml) average 10 year disease free rate for 3,478 patients. So according to Reference #9 the highest reported average 10 year 0.2 ng/ml RP disease free rate is 79%. References for evaluating serious urinary problems for RP treatment are #12, #13, #14 and g14. References #12, #13 and #14 identify incontinence rates from 8% to 17%. A review of Reference g14 ( RP) identified an incontinence rate of 8% for 1,870 patients. So based on Reference g14 the lowest reported incontinence rate reported for RP is 8%. The only reference for evaluating serious rectal problems for RP treatment was g14. Reference g14 ( RP) identified one rectal injury (0.05%) out of 1,870 patients which rounds down to 0%. So according to Reference g14 the lowest reported RP serious rectal side effect rate is 0%. References for evaluating serious sexual problems for RP treatment are #15, #16 and #17. References #15 ( RP), #16 ( RP) and #17 ( RP) identified a best average ED rate of 33% when both sex nerves were spared. So based on these references the lowest reported (1 year) ED rate for RP is 33%. Proton Beam References for evaluating average 10 year disease free results for Proton Beam treatment are #21 and #22. Reference #21 (2006) describes an average 10 year disease free rate for 1,255 patients of 73% (ASTRO) with an estimated 62% (0.2 ng/ml). Reference #22 (2004) describes an average 8 year disease free rate for the same 1,255 patients of 73% (ASTRO) and an estimated 62% (0.2 ng/ml). Even though they indicated the results were based on 8 year data one of the figures shows the same 73% rate at 8 years and 10 years. One of the questionable characteristics of ASTRO measures is that they artificially stay flat usually after 5 years when other measures, for the same group of patients, continue to drop in value over time. However, according to Reference #21 the highest reported average 10 year Proton Beam disease free rate was 73% (ASTRO) and 62% (0.2 ng/ml). 10

11 The only Reference that evaluated serious urinary problems for Proton Beam treatment was #22 (2004), which identified a 1% (total) Grade 3 and 4 serious urinary side effect. Therefore, Reference #22 documented a Proton Beam incontinence rate of 1%. The only reference that evaluated serious rectal problems for Proton Beam treatment is also #22, which identified a 1% (total) Grade 3 and 4 serious rectal side effects. So, Reference #22 documented a Proton Beam serious rectal side effect rate of 1%. There were no references that evaluated serious sexual problems for Proton Beam treatment so it is proposed that an estimated ED rate of 30% be used as a first approximation. External Beam (External Radiation) References for evaluating average 10 year disease free results for External Beam treatment are #3, #27, g4 and g5. Reference #3 (2005) identified an average 10 year EBRT disease free rate of 53% (ASTRO) and 45% (0.2 ng/ml). Reference #27 (2011- IMRT) identified a calculated average 10 year disease free rate of 76% (Nadir+2) and a (0.2 ng/ml) Nadir+2/(1.12) disease free rate of 68%. Reference g4 (2003) identified a 53% (8 year) 4,839 patient rate that when reduced by 5% to compensate for the 8 year data resulted in a 53%x0.95 = 50% (ASTRO) rate. Then converting the ASTRO rate to the 0.2 ng/ml rate resulted in a 50%/1.17 = 43% (0.2 ng/ml) rate. Reference g5 (2001), which utilized both 3DCRT and IMRT treatments identified low, intermediate and high risk 5 year results of 85%, 58% and 38% for 279, 405 and 416 patients (a total of 1,100 patients) resulting in an estimated 10 year average disease free rate of 57%x0.9 = 51% (ASTRO) and 51%/1.17 = 44% (0.2 ng/ml). So based on Reference #27 the highest reported average External Beam 10 year disease free rate was 76% (Nadir+2) and 68% (0.2 ng/ml). References for evaluating serious urinary problems for External Beam treatment are #27, g16, g20, g21, g22 and g23. Reference #27 (2011) indicated the serious urinary side effect rate for 170 patients was 1%. Reference g16 (1996) identified 3 out of 132 (2.3%) pre-treatment TURP patients and 1 out of 626 (0.2%) non TURP patients became incontinent, resulting in a total incontinence rate of 2.5%. Reference g20 (1998-3DCRT) also indicated slightly less than 1% of 743 patients experienced long term incontinence. Reference g21 (2002) indicated 772 patients experienced essentially 0% incontinence (although they may have excluded TURP patients from the study as they show up in nearly all other PCa treatment studies). Reference g22 (2002) was the same basic report as g21 but in a different format with a subset of the same authors and Reference g23 (1999) was an older version of g21. Note: the average disease free rate for Reference #27 was so much better than the other External Beam reports that the serious urinary side effect rate cited was taken from that report. So according to Reference #27 the External Beam serious urinary side effect rate is 1%. References for evaluating serious rectal side effect problems for External Beam treatment are #25, #27, g5, g15, g18, g20, g21 and g22; however, due to a significant reduction in 11

12 rectal side effects with IMRT, versus 3DCRT, only the IMRT results are compared. Reference #25 ( IMRT) indicated 1.6% of 561 patients experienced (Grade 2) rectal bleeding and 0% experienced Grade 3 rectal side effects. Reference #27 (2011) indicated the serious GI rate for 170 patients was 1%. Reference g5 (2001 IMRT part) indicated the overall rate of IMRT late Grade 2 and Grade 3 rectal toxicity was 2% and 0.5% respectively (compared to 3DCRT rates of 12% and 2%); Reference g15 (1998-3DCRT) was not utilized; Reference g18 ( External Radiation) was not utilized; Reference g20 (1998-3DCRT) was not utilized; Reference g21 (2002 IMRT) indicated that 35 out of 772 patients (4.5%) developed acute Grade 2 rectal toxicity and 0% experienced acute Grade 3 or higher rectal symptoms; Reference g22 ( IMRT) which compared 3DCRT treatment of 61 patients with IMRT treatment of 171 patients at the same dose level reported 2 year 10% actuarial rates of Grade 2 rectal bleeding for 3DCRT and 2% for IMRT (with one case of Grade 3 rectal bleeding for 3DCRT (1.6%) and one case for IMRT (0.6%). So according to Reference #25 and g21 the lowest External Radiation (IMRT) serious rectal side effect rate is 0%. References for evaluating serious sexual problems for External Beam treatment are #25, #27, g23, g35 and g36. Reference #25 ( IMRT) reported an ED rate of 49%. Reference #27 ( IMRT) reported a 10 year ED rate of 44% but since there is no credible way to translate a 10 year ED rate to a 5 year or less rate it will not be used. Reference g23 (1999-3DCRT) reported a five year ED rate of 43%. Reference g35 ( External Beam) reported an ED rate of 62%. Reference g36 ( Interstitial Radiotherapy) reported a 1.5 year ED rate of 45%. So according to Reference g23 the lowest five year ED rate for External Beam treatment is 43%. External Radiation before Seeds (IMRT>Seeds, EBRT>Seeds or 3DCRT) References for evaluating average 10 year disease free results for External Radiation before Seeds treatment are #19, #20 and g11. Reference #19 (1998) described both Seeds Only and EBRT>Seeds treatment, where the combined 10 year average disease free result for both treatments was 65% (0.5 ng/ml). The EBRT>Seeds group consisted of 52 patients and the 0.5 ng/ml measurement which can t be related to either ASTRO or 0.2 ng/ml measurements. Even so, it was a pivotal study because the EBRT>Seeds treatment for higher risk patients produced better 10 year results than the Seeds Only treatment for lower risk patients. This study helped shape future treatments towards improving combined external and internal PCa radiation treatment, in either order. Reference #20 (2006) described a 3-D Conformal Radiation Therapy 3DCRT>Seeds treatment where 119 intermediate and 124 high risk patients were treated with 3DCRT followed by I-125 implants resulting in an average 10 year ASTRO disease free rate of 81% and a converted 0.2 ng/ml disease free rate of 69%. A review of Reference g11 (2003 -EBRT>Seeds) treatment where 232 patients were treated with EBRT followed 4 weeks later with I-125 or Pd-103 implants resulted in an average 10 year ASTRO disease free rate of 70% (based on 2 not 3 consecutive PSA rises). So the highest reported average EBRT>Seeds and 3DCRT>Seeds 10 year disease free rate from Reference #20 was 81% (ASTRO) and 69% (0.2 ng/ml). 12

13 References for evaluating serious urinary issues for External Radiation before Seeds treatment were #20 and g39. Reference #20 (2006-3DCRT>Seeds) treatment morbidity was limited to temporary 3-6 month Radiation Therapy Oncology Group (RTOG) Grade 1-2 urinary and rectal symptoms. In addition, one patient that had both a pre-treatment Transurethral Incision of the Prostate (TUIP) and a post-treatment TURP developed low volume stress incontinence (1/243)x100% = 0.41%, which would normally round down to 0%. However, about 8% of all TURP patients (about 1% of a normal PCa patient treatment distribution) experience serious urinary problems so the 0.41% value was in this case rounded up to 1%. Reference g39 ( IMRT>Seeds) identified that out of 131 patients 10 (1%) experienced Grade 3 or greater acute urinary toxicity. Therefore, according to both Reference #20 and g39 the lowest reported serious EBRT>Seeds urinary side effect rate is 1%. References for evaluating serious rectal problems for External Radiation before Seeds treatment are #20 and g33. Reference #20 indicated there was 0% rectal fistula or ulcerations. Reference g33 reported Gastro Urological and Gastro Intestinal (GU/GI) serious side effects as a single number although four of the nine cases reported were described later in the text as being caused by rectal proctitis, which based on 130 patients studied is 4/130 = 3%. So according to Reference #20 the lowest reported EBRT>Seeds serious rectal side effect rate was 0%. The only reference for evaluating serious sexual problems for External Radiation before Seeds treatment is g39. Reference g39 (2006 IMRT>Seeds) identified a post-treatment ED rate for 29 of 61 non-androgen deprivation men that were potent at the time of treatment of 48% and 46% at 18 months. So according to g39 the lowest 1.5 year ED rate for 3DCRT>Seeds treatment is 46%. HDR>EBRT The only reference for evaluating average 10 year disease free results for High Dose Rate (HDR)>EBRT treatment is #23 (2005). A more recent HDR>IMRT report was found but that report did not meet the 10 year criteria. Reference #23 ( HDR>EBRT) treatment consisted of 209 patients that were treated twice during a one week period using removable HDR radiation probes, followed two weeks later with 20 EBRT treatments over a four week period. Reference #23 indicated the average 10 year treatment result was 79% (ASTRO) and 68% (0.2 ng/ml). However, it also identified average 10 year ASTRO disease free rates of 90%, 87% and 69% for 70, 92 and 47 low, intermediate and high risk patients which resulted in a calculated all risk 10 year (ASTRO) rate of 84%. Finally, they reported a Kaplan-Meier average 10 year ASTRO disease free rate of 81%. So it was decided to only use the lowest average #23 10 year disease free rate of 79% (ASTRO) and 68% (0.2 ng/ml). The reference for evaluating serious side effects for HDR>EBRT treatment was also #23. The HDR>EBRT entries for serious urinary, rectal and ED side effects were 5%, 1% and 39%. So based on Reference #23 the lowest reported HDR>EBRT serious urinary, rectal and ED rates are 5%, 1% and 39%. 13

14 Cryosurgery (Cryotherapy) References for evaluating average 10 year disease free results for Cryosurgery treatments are #26, g12 and g13. Reference #26 (2008) describes Prostate Cryoablation treatment where 1,198 patients achieved an average 5 year ASTRO disease free rate of 77.1% (one more exception to the 10 year treatment rule); so an estimated 10 year ASTRO disease free rate would be 77.1%x0.90 = 69.4% (69%) with an estimated average 10 year 0.2 ng/ml rate of 69.4%/1.17 = 59.3% (59%). Reference g12 (2002) describes a treatment where 590 patients were treated with Targeted Cryoablation of Prostate Cancer (TCAP) with 15.9% low risk patients, 30.3% intermediate risk patients and 53.7% high risk patients. The corresponding ASTRO seven year disease free rates were 92%, 89% and 89%. However, these values do not appear valid because they don t follow the traditional pattern of lower treatment results for higher risk PCa. Later they mentioned that when the three risk groups were measured against the 0.5 ng/ml criteria the results were 61%, 68% and 61% which is also an unusual result so all were rejected. Reference g13 (2001) describes Cryosurgery treatment results where a total of 975 patients from 5 different treatment centers underwent Cryosurgical Ablation of the Prostate (CSAP) with 25% low risk, 34% medium risk and 41% high risk patients. The 0.5 ng/ml 5 year disease free result (apparently for just the low and intermediate risk level results) was 45% and 36%. They also mentioned 1.0 ng/ml results but even those results do not appear to be credible so none of them were used. According to Reference #26 the best reported Cryosurgery disease free rate is 69% (ASTRO) and 59% (0.2 ng/ml). References for evaluating serious urinary side effects for Cryosurgery treatment are #26, g12, g13. Reference #26 (2008) described Prostate Cryoablation treatment where 1,198 patients experienced an average incontinence rate of 4.8% (5%). Reference g12 identified that 533 (out of a total of 590) patients were continent before treatment and 448 regained continence after treatment, with an average recovery time of 6.1 months; therefore, 16% remained incontinent. Reference g13 (2001) described Cryosurgery treatment results with an incontinence rate of 7.5%. So based on Reference #26 the lowest documented Cryosurgery incontinence rate is 5%. References for evaluating serious rectal side effects for Cryosurgery treatment are #26, g12 and g13. Reference #26 (2008) identified a rectal fistula rate of 0.4% (0%). Reference g12 (2002) identified less than 0.4% (0%) of 590 patients experienced serious rectal problems. Reference g13 (2001) identified 0.5% of 975 patients experienced serious rectal problems. So according to References #26 and g12 the lowest documented Cryosurgery serious rectal side effect rate is 0%. References for evaluating serious sexual side effects for Cryosurgery treatment are #26, g12 and g13. Reference #26 (2008) identified an ED rate of 75%. Reference g12 (2002) identified an ED rate of 95%; Reference g13 (2001) identified an ED rate of 93%; and So Reference #26 documented that the lowest (1 year) Cryosurgery ED rate is 75%. 14

15 Conclusion A detailed comparison of 61 applicable PCa treatment references permitted a more complete review of long term PCa treatments than previously possible. Summary Charts A, B, C and D are expected to provide more accurate PCa treatment comparison detail. This expanded set of studies continue to indicate that individual PCa treatments can have a wide range of results so it is advisable that men diagnosed with PCa examine their treatment choices carefully, including Active Surveillance for low risk patients. Finally, according to Reference g7 the pre-treatment potency for 1,166 PCa patients dropped from 70% for men to 25% for men over 80 resulting in a thirty year (70% - 25%) = 45% drop in potency simply due to aging. Therefore, since men near the median PCa detection age of 65 to 69 appear to lose sexual potency at a rate of about 1.5%/year even without PCa treatment; it should be possible to adjust published PCa treatment ED rates to a common 1 year value, where 5 year ED results would be reduced by a total of -4x1.5% = -6% and 3 year ED results would be reduced by a total of -2x1.5% = -3%. This would permit a more uniform comparison of PCa treatment ED rates (as implemented below and in the PCa treatment comparison charts presented earlier). Individual treatment type results are summarized next: Seeds before External Radiation (Seeds>IMRT or Seeds>EBRT) Ref. #5 identified an average 10 yr disease free rate of 83% (0.2 ng/ml). Ref. g29 identified an acute urinary incontinence side effect rate of 1%. Ref. g29 identified a serious rectal side effect rate of 0%. Ref. #6 identified an ED (1 year) side effect rate of 23% - 2x1.5% = 20%. Seeds Only (Brachytherapy) Ref. #2 identified an avg 10 yr disease free rate of 73% (ASTRO) and 62% (0.2 ng/ml). Ref. g23 identified an acute urinary retention side effect rate of 3%. Ref. g23 identified a serious rectal side effect rate of 0%. Ref. g7 identified an (1 year) ED side effect rate of 24% - 4x1.5% = 18%. Radical Prostatectomy (RP) Ref. #9 identified an average 10 year disease free rate of 79% (0.2 ng/ml). Ref. g14 identified an incontinence side effect rate of 8%. Ref. g14 identified a serious rectal side effect rate of 0%. Ref s #15, #16 and #17 identified a (1 year) ED side effect rate of 33%. Proton Beam Ref. #21 identified an avg 10 yr disease free rate of 73% (ASTRO) and 62% (0.2 ng/ml). Ref. #21 identified an acute urinary incontinence side effect rate of 1%. 15

16 Ref. #21 identified a serious rectal side effect rate of 1%. No Reference identified an ED side effect rate; suggest using a (1 year) estimate of 30%. External Beam (External Radiation) Ref. #27 identified an avg 10 yr disease free rate of 76% (Nadir+2) and 68% (0.2 ng/ml). Ref. #27 identified a serious urinary side effect rate of 1%. Ref. #27 identified a serious rectal side effect rate of 1%. Ref. g23 identified a (1 year) ED side effect rate of 43% - 4x1.5% = 37%. External Radiation before Seeds (IMRT>Seeds, EBRT>Seeds or 3DCRT>Seeds) Ref. #20 identified an avg 10 yr disease free rate of 81% (ASTRO) and 69% (0.2 ng/ml). Ref s #20 and g39 identified an acute urinary incontinence side effect rate of 1%. Ref. #20 identified a serious rectal side effect rate of 0%. Ref. g39 identified an (1 year) ED side effect rate of 46% - 0.5x1.5% = 45%. HDR>EBRT Ref. #23 identified an avg 10 yr disease free rate of 79% (ASTRO) and 68% (0.2 ng/ml). Ref. #23 identified an acute urinary incontinence side effect rate of 5%. Ref. #23 identified a serious rectal side effect rate of 1%. Ref. #23 identified an ED (1 year) side effect rate of 39%. Cryosurgery (Cryotherapy) Ref. #26 identified an avg 10 yr disease free rate of 69% (ASTRO) and 59% (0.2 ng/ml). Ref. #26 identified an acute urinary incontinence side effect rate of 5%. Ref s #26 and g12 identified a serious rectal side effect rate of 0%. Ref. #26 identified an ED (1 year) side effect rate of 75%. PSA Group Bias The following rational provides an approach for adjusting average 10 year disease free results by compensating for average patient PSA group bias. More elegant approaches using PSA, Gleason and Staging risk level distributions can also be used. The PSA group method described below results in RP versus all other treatment risk level bias treatment rate adjustments from 1.00 to 1.07 as summarized in Chart A. a. Seeds>IMRT (and Seeds>EBRT) STEP 1a: The first PCa treatment to be compared is Seeds before IMRT performed at RCOG = 83% (compared to RP at Johns Hopkins = 77%). The men treated at those centers had the following pre-treatment PSA distributions: 16

17 Treatment / PSA Dist. 0 to to to Seeds>IMRT % 66.0% 21.3% 5.7% RP (@ JH) % 51.6% 16.9% 4.8% STEP 2a: A non peer reviewed study by RCOG in 2007 identified average 10 year 0.2 ng/ml disease free results for the four PSA groups listed above as 98%, 90%, 75% and 54%. Using this data to hypothetically calculate PCa treatment results (in 2007) permits the determination of non RP patient group PSA treatment difficulty distributions relative to Johns Hopkins RP patient distributions (this step is the same for all other following comparisons and is only described here). STEP 3a: Apply Step 2a cure rates to the distribution of patients in Step 1a. Doing this allows the computation of an estimated 2007 average disease free rate for both patient groups as if they had been treated at the Step 2a facility. Seeds>IMRT = 98%x %x %x %x0.057 = 85.3% RP (@ JH) = 98%x %x %x %x0.048 = 87.9% This means that Johns Hopkins RP patients would have been easier to treat than the Seeds>IMRT patients by a factor of 87.9/85.3 = STEP 4a: The 83% Seeds>IMRT average 0.2 ng/ml 10 year disease free rate needs to be multiplied by 1.03 to compensate for their patients being more difficult to treat than RP patients at Johns Hopkins. This means that the Seeds>IMRT disease free rate would need to be increased to 83%x1.03 = 86%. b. Seeds Only STEP 1b: The next treatment to be examined for patient risk bias is Seeds Only (ASTRO adjusted) = 62% average 10 year 0.2 ng/ml disease free rate. The men treated at these centers had the following average pre-treatment PSA distributions: Treatment / PSA Dist. 0 to to to Seeds Only - Avg 25.9% 53.3% 14.8% 6.0% RP (@ JH) % 51.6% 16.9% 4.8% STEP 3b: Apply Step 2a cure rates to the distribution of patients in Step 1b. Doing this allows the computation of an estimated 2007 average disease free rate for both patient groups as if they had been treated at the Step 2a facility. Seeds Only = 98%x %x %x %x0.060 = 87.7% RP (@ JH) = 98%x %x %x %x0.048 = 87.9% This means that Johns Hopkins RP patients would have been easier to treat than the Seeds Only patients by a factor of 87.9/87.7 = =