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DrBlasko Low/IntermediateRiskProstateCancer(Sky/Teal)

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It is important to understand that prostate cancer is not a single disease but a spectrum of diseases. Treatment considerations, therefore, must be individualized to each person’s particular situation. Patients diagnosed with Low or Intermediate Risk disease are faced with multiple choices for management. Low Risk (SKY in the Shades of Blue classification scheme) is usually defined as stage T1 – T2a, Gleason score < 6 and PSA < 10. Intermediate Risk (TEAL in the Shades of Blue classification) is defined as having one of the following: stage T2b, Gleason score 7, PSA 10 – 20. Additional diagnostic information such as percent positive biopsy cores, perineural invasion and modern imaging results are useful in further refining the status of the disease. . What is unique for Low and most Intermediate Risk is that treatment may be either unnecessary or delayed because the disease can be so small and slow growing that it does not threaten the life of the patient. Further, there is data to suggest that death from prostate cancer at this stage is rare even if it is not eradicated. The question is how can you be sure of this and are you comfortable with this idea of not treating a cancer?
Many men are not comfortable with no treatment in these risk groups and opt for some form of definitive treatment at the time of diagnosis such as surgery, brachytherapy, or external beam radiation. . Lacking airtight randomized studies comparing treatments, a great deal of work has gone into analyzing the available literature for outcomes and complications of these three approaches. It is this author’s opinion that review of the literature supports brachytherapy as offering the highest probability of cure with the least long-term complications in patients who are suitable for this approach.
For patients who wish to avoid or at least delay the risks of definitive treatment, they may wish to consider some form of disease monitoring such as Active Surveillance. . There is exciting research being done with multi-parametric MRI scanning that in the future may allow us to accurately monitor prostate cancer without the invasiveness of biopsies. If disease does advance, some studies show that treatment at that time is as effective as treatment would have been initially.
Patients with Low or Intermediate Risk prostate cancer are faced with many decisions and choices that can be confusing and anxiety provoking. It is important to work with a knowledgeable physician to help guide you through this labyrinth. The good news is that patients with this category of disease very rarely die of prostate cancer no matter what choices are made and if definitive treatment is done, the chances of complete cure is over 90%.

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DrBlasko Low/IntermediateRiskProstateCancer(Sky/Teal)

  1. 1. TREATMENT CONSIDERATIONS FORLOW INTERMEDIATE RISK / PROSTATE CANCER John Blasko MD
  2. 2. Diagnosing a Shade of Blue * One core > 50% replaced with cancer bumps to Teal ** Two yellow boxes bumps Teal to Azure*** Any rising PSA with a low testosterone bumps to RoyalECE = Extra-capsular Extension, SV = Seminal Vesicle, PN = Pelvicnode
  3. 3. Shades: The Question of TreatmentWith occasional exceptions, men below the blue dottedline always require treatment. Men above the bluedotted line may or may not require treatment Low Risk Sky Treatment vs.Intermediat Teal no treatment? e High Azure Relapsed Indigo Treatment Advanced Royal
  4. 4. Treatments for Prostate Cancer Surgery- robotic or not (studies show no difference) Radiation  Seed implantation  Permanent Seeds  Iodine  Palladium  Cesium  Temporary High Dose Rate (HDR) Seeds  Beam Radiation  IMRT (conventional, accelerated, hypofractionated)  Proton
  5. 5. Surgery
  6. 6. The Prostate is “Built In” Surgical Access is Difficult Pubic BoneUrethra BladderIntestines
  7. 7. Robotic Prostatectomy  Computer enhanced  Surgeon operates at the console within a 3D view  Bedside surgical assistant is next to the patient  Instruments move like a human wrist (↑ dexterity and precision)
  8. 8. Surgeon Directs Instruments  The surgeon’s hands are placed in special devices that direct the instrument movement
  9. 9. BladderAnatomy of the Neurovascular BundlesTo preserve sexual potency, the goal is toavoid cutting the nerves
  10. 10. Surgery Pros and ConsPros Learn more about cancer status Some men feel better about “having it out” Long experienceCons Major operation Greater chance of incontinence and
  11. 11. Radiation- Brachytherapy: Permanent Seeds High-Dose Rate Afterloading- Beam Radiation: IMRT (conventional and accelerated) Hypofractionated (cyberknife)- Protons
  12. 12. Seeds
  13. 13. Seed Implant ProcedurePreloaded Needles Mick Applicator
  14. 14. Implant Procedure
  15. 15. X-Ray of Patient after Completing a SeedImplant
  16. 16. prostate urethraPeripheral Placement of Seeds to AvoidUrethra
  17. 17. High-Dose-Rate Afterloading: Temporary Iridium-192 Brachytherapy1. HDR afterloader; Ir-192 source on cable 2. Needle insertion by TRUS guidance3. Implant completed; CT planning 4. Implant needles attached to HDR afterloader
  18. 18. Catheters in place for hours to days
  19. 19. Brachytherapy Pros and ConsPros Delivers highest biologic dose of radiation Most convenient and least disruptive Less chance of long term complicationsCons Requires expertise and experience Short term urinary side effects
  20. 20. Linear AcceleratorExternal Beam Radiation(IMRT and Accelerated IMRT)
  21. 21. Intensity Modulated Radiation Therapy (IMRT)
  22. 22. “Cut Away” View of IMRT Showing DoseDistribution
  23. 23. External Beam Radiation Pros andConsPros Widely available Technical advances Generally easy treatmentCons Radiation dose is limited Standard treatment is time consuming Risk of rectal injury
  24. 24. Goals of Treatment- Cure the disease- Prevent suffering- Minimize impact on quality of life
  25. 25. Cure: What is its significance?Cure does not necessarily mean longersurvival. The majority of men with prostatecancer who have a relapse after treatment dieof causes unrelated to prostate cancer.
  26. 26. Summary of >100 Studies Looking at 5-year Cure Rates of Different Treatments 18,000 prostate studies published between 2000 and 2010 848 studies reported treatment results 140 of those studies met the following criteria: 1. Reported on 100 or more patients 2. Results reported for Low, Intermediate and High- Risk 3. Minimum of five years of follow up
  27. 27. Cure Rates with Seed Monotherapy Intermediate Risk: Teal 100 33 33 23 13 14 14 23 13 37 37 90 44 44 16 16 39 39 6 12 6 12 42 42 80 17 17 BrachyAlone Seeds Surgery 70 29 29 EBRT 11 11 46 CRYO 60 46 HIFUs ecc u St ne maer T 50er gor P ASP % ← Years from Treatment → t 40 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 •Numbers within symbols refer to references
  28. 28. Seed Monotherapy vs. Surgery*: Teal (Intermediate Risk) 1 0.9 24 1540 8 Brachy 23 0.8 2 17 37 12 22 Brachy 4 40Percentage 0.7 16 Relapse 3612 Surgery 0.6 34 32 Surg Free 31 43 8 0.5 no ss er gor P % 0.4 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Years after Treatment i *Grimm, BJU Int, 2012, Vol. 109(Supp 1)
  29. 29. Cure Rates Intermediate Risk: Teal 14 33 14 33 13 13 EBRT + Seeds 37 37 Robot RP 31 31 35 35 34 34 90 1544 1544 + + Seeds + HT 38 40 Seeds Alone 3240 36 45 36 45 4 4 38 EBRT & Seeds 32 77 39 39 12 16 12 16 42 42 80 43 43 3 3 17 17 Hypo EBRT 18 18 28 Brachy Seeds Alone EBRT 6 5 28 6 5 9 9 70 7 25 7 4125 29 41 1 29 Surgery Surgery 1 2 2 10 10 11 46 11 46 60 EBRT 20 8 20 8s ecc u St ne maer T HDR 50er gor P ASP % ← Years from Treatment → t 21 21 40 22 22 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 29
  30. 30. 100 21 8 8 14 21 14 20 20 23 23 Brachy 4 4 17 10 17 10 90 19 19 16 5 EBRT & 16 5 26 12 26 24 12 Seeds 24 7 7 22 22 Robot RP Surgery 3 3 9 9 18 Brachy 80 25 25 18 15 13 15 13 11 11 Surgery 13 13 EBRT 2 2 EBRT CRYO 70 HIFU Protonsgor P ASP % ← Years → No TX 60 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 • Prostate Cancer Results Study Group 3/31/09 • Numbers within symbols refer to references09/14/12 30
  31. 31. Conclusion on Cure Rates:Modern seed implants result incure rates that appear slightlybetter than surgery
  32. 32. Comparing Long-Term SideEffectsWhat percentage of men recovernormal urinary and sexual function(similar to before treatment) aftersurgery or radiation?
  33. 33. Return to Baseline Urinary Function Schellhammer, J Urol 183:1822, 2010 Brachytherapy or Cryotherapy Robotic or Open Surgery Months after Treatment
  34. 34. Return to Baseline Sexual Function Schellhammer, J Urol 183:1822, 2010 Brachytherapy Surgery or Cryotherapy
  35. 35. Return to Baseline Urinary Control Gore , JNCI 101:888, 2009
  36. 36. Return to Baseline Sexual Function Gore , JNCI 101:888, 2009
  37. 37. Sexual Distress of 625 Spouses Sanda, NEJM 358:1250, 2008 Type of Median Age of % of PartnersTreatment Patient DistressedSurgery 59 44%Radiation 69 22%Seed 65 13%Implants
  38. 38. QOL after 5 years: Surgery vs. Seeds Crook J Clin Onc 29:362, 2010 Compared to surgery, seeds implants showed significantly better:  Urinary function  Sexual function  Overall patient satisfaction There was no difference in bowel function between seeds and surgery
  39. 39. Study of Side Effects: IMRT vs. Proton Sheets, JAMA 307:1611, 2012 Study evaluated the incidence of GI, urinary, sexual function in 6600 men treated with IMRT and 684 men with Proton between 2002 and 2007 IMRT was associated with a lower incidence of gastrointestinal morbidity compare to Proton There was no difference between the two treatments in sexual or urinary function
  40. 40. Accelerated IMRT 2.5 Gy in 5 weeks (Kupelian, IJROBP 68:1424, 2007)  3.1% grade 2 rectal toxicity  5.1% grade 2 urinary toxicity 3.1 Gy in 4 weeks (Lock, IJROB 80:1306, 2011)  25% grade 2 and 3% grade 3 rectal toxicity  14% grade 2 and 5% grade 3 urinary toxicity
  41. 41. Conclusion: Quality of Life Chances for complete recovery of sexual function are better after seed implantation than they are after surgery Chances for complete recovery of urinary function are better after seed implantation than after surgery Chances for normal bowel function are better after seeds than after external beam
  42. 42. Comparison of Treatments “The Gold Standard” Surgery was the “Gold Standard” in the 1990s when radiation was ineffective and toxic  Surgical cure rates were better  The side effects of surgery were less Seed implantation is the new “Gold Standard” in the modern era. Compared to surgery:  Cure rates from seeds are at least as good  Side effects of seed implantation are less than surgery
  43. 43. Cure Rates = Mortality RatesProstate cancer tends to be an indolentdisease, even if it isn’t cured. The majorityof men who develop a relapse after surgeryor radiation die of causes other thanprostate cancer (mainly heart disease).
  44. 44. Cancer Specific Survival after Treatment (I rm e d ia te -Ris k: Teal) nte 8 years: 1019 men (Zelefsky, JCO 28:1508, 2010)  Surgery: 98.1%  External beam 95.5%* 10 years: 10,500 men (Kibel, J Urol 187:1259, 2012)  Surgery: 98.2%  External beam: 97.1%  Seed implant: 97.7% *In the Zelefsky study, patients initially treated with radiation and who subsequently relapsed had delayed salvage treatment compared to patients who relapsed after surgery
  45. 45. Dangerous Types of Prostate Cancer Can be Indentified in Advance Eggener, Journal of Urology 185:869, 2011 Different Types of PC 15-Yr. MortalityGleason 6 0.2-1.2%Gleason 8 - 10 26-37%Seminal Vesicle Invasion 15-27%Lymph Node Metastases 22-30%Only 3 men of 10,000 who had Grade 6, organ-confined disease died of prostate cancer
  46. 46. Predicting Prostate Cancer Mortality(PCSM) Stephenson, Journal of Clinical Oncology 2009“Only 4% (1 in 25) of contemporary patients have a PCSM risk greater than 5%”
  47. 47. To Treat or Not To Treat Low/Interm. RiskWhitmore’s Conundrum“The quandary in prostatecancer: is cure necessary inthose for whom it is possible,and is cure possible in thosefor whom it is necessary?”1988 Willet Whitmore, Jr, MD Father of Urologic Oncology
  48. 48. Management Choices for Low/ Interm Risk MonitoringObservation Active Surveillance Definitive TreatmentWatchful WaitingNo testing. Periodic testing. Treat to eradicateTreat only when and Definitive treatment the disease.if symptoms develop. if progression.
  49. 49. “Watching” Palpable Disease Connecticut study: 20-year death rate of men diagnosed in the 1970’s was 7%  JA A2 0 0 5 M Swedish study: 15-year death rate of men with well-differentiated prostate cancer was 2.5%  JA A1 9 9 7 M
  50. 50. PIVOT Trial: Surgery vs. “Observation” Wilt, NEJM 367:203, 2012 731 men randomized between1994 to 2002 Cancer detected by PSA testing Average age = 67, median PSA = 7.8 Half the men had Gleason 7 or above Half the men had a palpable nodule Two-thirds were I nte rm e d ia te -Ris k or Hig h-Ris k
  51. 51. Outcome Ten Years Later Wilt, NEJM 367:203, 2012 # Men Cancer Cancer Severe Potenc Dead Death Death Loss y from Rate Rate Urinary Gone Cancer Overall (PSA>10 Control ) Surgery 21 5.8% 5.6% 17% 81% 364 men Observ. 31 8.4% 12.8% 6% 44% 367 menAdditional side effects of surgery: 1 death, 2 blood clots, 1 stroke,2 lung emboli, 3 heart attacks, 1 on kidney dialysis, 10 requiredadditional surgery, 5 had serious infections, 17 had wound infectionsor UTI, 6 had a urinary catheter for > 1 mo. and 6 blood transfusions.
  52. 52. Scandinavian Trial: Surgery vs. No Treatment Bill-Axelson, NEJM 364:1708, 2011  695 men randomized between1989 & 1999  Cancer detected by rectal examination (DRE)  88% had a palpable abnormality on DRE  Average age 65, average PSA was 13  One-third of the men had Gleason 7 or more  Death rate @ 15 years 6% lower in men
  53. 53. Scandinavian Trial: Surgical Complications Bill-Axelson, NEJM 364:1708, 2011Complication in 289 Number Incidence 1 YearMen of Events after SurgeryUrinary Leakage or 99 34.3%BlockageImpotence 168 58.1%Leg or Lung Blood 7 2.4%ClotsDeath from Surgery 1 0.3%
  54. 54. “Observation” = Active Surveillance Observation Active Surveillance Aim Avoid treatment Individualize therapy Monitoring Lax Aggressive Indications for Cancer symptoms PSA increase, treatment such as bone pain changes on ultrasound or biopsy Treatment timing Late Early Treatment intent Symptom control Cure
  55. 55. The Advantage of Active Surveillance: Accurate Selection of Men Who Need Treatment At initial diagnosis, treatment decisions are made by looking at a “single frame” from the whole movie Changes in predictive factors such as Gleason, PSA and imaging o ve r tim e enable treatment decisions to be tailored to the tumor biology in e a c h ind ivid ua l
  56. 56. Study of Active Surveillance Klotz, JCO 28:126, 2010 450 men monitored from 1 to 13 years Median age 70; Median PSA between 5 to10 71% Lo w-Ris k; 29% I rm e d ia te -Ris k nte 10-year cancer survival was 97.2%--5 men died of prostate cancer. Four of the five were treated within 2 years of initial diagnosis 117 patients had surgery or radiation and their cure rate was 50%
  57. 57. Non–Prostate Cancer Mortality vs. Prostate Cancer Mortality. Ratio was 18.6 to 1 Klotz, JCO 28:126, 2010XXX
  58. 58. X XCure Rates with Surgery or Radiation X after X Active Surveillance X Xx Klotz, JCO 28:126, 2010 X #35 p = n.s. #90
  59. 59. Study of Active Surveillance Tosoian , JCO 29:2185, 2011 769 men monitored from 1 to 15 years Median age 66; Median PSA was 5 All Gleason six; most with 2 or fewer cores positive No cancer deaths, no occurrence of metastases 192 had surgery or radiation of whom 18 (9.4%) have had a PSA relapse
  60. 60. Cure Rates with Surgery orRadiation after Active Surveillance Tosoian , JCO 29:2185, 2011
  61. 61. For Whom is Surveillance a Safe Option?Slide Provided by Laurence Klotz
  62. 62. National Comprehensive Cancer Network (NCCN) Practice Guidelines Mohler et al, J Natl Compr Canc Netw. 2010ECURRENCE RISK EXPECTED INITIAL RISK SURVIVAL THERAPY Very Low Active <20yr Surveillance (Epstein Criteria) Preferred Low Risk 1) Active Surveillance >10yr 2) Radiotherapy (D’Amico Criteria) 3) Radical Prostatectomy Slide Provided by Laurence Klotz
  63. 63. Monitoring Protocols of Different Centers  Klotz  DRE/PSA every 3 months for 2yrs, then every 6 months  Biopsy 6-12 months after enrollment, then every 3-4yrs  Multi-institutional (Univ Miami, Univ British Columbia; MSKCC; Cleveland Clinic)  DRE/PSA every 6-12 months  Biopsy 18 months after enrollment, then every 1- 3yrs  Johns HopkinsSlide Provided by Laurence Klotz  DRE/PSA at 6 month intervals
  64. 64. Surveillance vs. Surgery vs. IMRT vs. BrachytherapyComparative Effectiveness and Value Institute for Clinical and Economic Review Massachusetts General Hospital
  65. 65. Results of Surgery after Active Surveillance Duffield, J Urol 182:2274, 2009 100% of men with tumor volume > 1.0 cm were located in the anterior portion of the prostate, “out of reach” to a standard 8-12 core biopsy MRI directedStandard or Color Doppler Biopsy ultrasound directed biopsy can Prostate Prostate diagnose anterior tumors Rectum Rectum
  66. 66. Future Directions: Monitoring with Imaging Instead of Repeated Biopsy? AUA Abstracts 2012  Abstract #2051: 179 men diagnosed with a 14- core biopsy. Multi-parametric MRI prior to the biopsy only missed one case of low volume high grade disease (Case was low volume 4 + 4 = 8)  Abstract #1444: 64 men evaluated with multi- parametric MRI prior to a template mapping biopsy. MRI predicted the absence of Gleason above 3 + 4 = 7 with 95% accuracy
  67. 67. Individual Factors Affecting Treatment Choice, But Not Addressed in this Talk Patient factors:  Advanced age  Comorbidity health issues  Previous abdominal surgery Sexual factors:  Baseline Potency  Libido and sexual interest  Partner’s sexual availability and libido Prostate factors:  Prostate size  Preexisting urinary symptoms  Previous history of transurethral resection (TURP)
  68. 68. Conclusions RegardingTreatment for Low/Intermediate Risk Since mortality rates are low, treatment selection should be influenced much more by quality of life considerations than by survival concerns The pros and cons of all the different alternatives need to be evaluated in light of each individual’s priorities and unique clinical profile Delaying immediate treatment and taking time to learn about all the various options is usually a wise initial course of action.

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