Module 6 Dr Scholz-HormonalTherapies


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  • During ADT,
  • Module 6 Dr Scholz-HormonalTherapies

    1. 1. Mark Scholz, MDPCRI Mentor Class 2012 1
    2. 2. Testosterone InactivatingPharmaceuticals (TIP) Other names for TIP: Androgen Deprivation Therapy (ADT) Hormone Blockade (HB) Androgen Blockade (AB) Androgen Suppression Therapy (AST) 2
    3. 3. What Other Anti-Cancer Therapy InducesRemissions Lasting More than a Decade? Cancer Type Life Expectancy after Relapse Pancreatic cancer 4 months Kidney cancer 6-8 months Stomach cancer 8-10 months Lung cancer 12-14 months Colon cancer 24 months Prostate cancer 160 months! 3
    4. 4. TIP Maintains a Low and Stable PSA foran Average of Ten Years After Relapse PSA relapse: Surgery or Hormone Start TIP radiation resistance Average 3 10 years years or so 4
    5. 5. How Does Testosterone Deprivation Work? 5
    6. 6. Six Types of Anti-Testosterone Therapy1. Proscar & Avodart 5-alpha reductase inhibitors Block DHT synthesis from testosterone DHT is 5-10 times more potent than testosterone1. Casodex, Nilutamide & Flutamide Anti-androgens: Block androgen receptor Blood testosterone remain normal or rise 6
    7. 7. Six Types of Anti-Testosterone Therapy (cont.)3.Lupron, Trelstar, Eligard, Zoladex, Vantas & Firmagon LHRH agonists and antagonists Block testicular production of testosterone Essentially the same net effect as orchiectomy though blood testosterone is slightly lower with Lupron: (van der Sluis, J. Urol. 187:1601, 2012)4. Estrogens: DES, Estrogen Patches (Vivelle Dot) Block testicular production of testosterone and Also sharply increase the levels of sex hormone binding globulin (SHBG) in the blood. SHGB binds and inactivates testosterone 7
    8. 8. Six Types of Anti-Testosterone Therapy(cont.)5. Zytiga (abiraterone), Nizoral (ketoconazole) Block testosterone synthesis in the cancer cell Can affect the blood levels of other medications including statins6. MDV-3100 (Pending FDA approval) Blocks the androgen receptor Estimated to be 20 times more potent than Casodex 8
    9. 9. Ascending Levels of TIP Potency1. Mild—Avodart & Proscar2. Moderate—Casodex, Nilutamide & Flutamide (Anti-androgen monotherapy)3. Stronger—Lupron, Zoladex, Trelstar, Estrogen4. Even stronger—#1 + #2 + #35. Most Potent—Zytiga, MDV-3100 (plus Lupron)6. Even More Potent?—Zytiga plus Nilutamide or Zytiga plus MDV-3100? 9
    10. 10. Roles for Testosterone DeprivationPreliminary to radiation to reduce prostate sizeAncillary to radiation (or surgery) to improve cure rates  Intermediate-Risk  High-Risk  PSA-Relapsed diseaseAs standalone therapy  Intermediate-Risk  PSA-Relapsed disease  Advanced diseaseSecond-line therapy  Zytiga  Nilutamide  Ketoconazole 10
    11. 11. TIP to Shrink the Prostate Gland Prior to RadiationMen receiving three months of Casodex and Avodart had prostate size reduced by an average of 33% (Merrick, UROLOGY 68:116, 2006)Men receiving 3 months of TIP before seeds benefited with reduced AUA scores lasting up to 3 years after implantation compared to men not receiving TIP (Stone, J. Urol. 183:634,2010) 11
    12. 12. Intermediate-Risk High-Risk PSA-Relapse 12
    13. 13. TIP with Radiation: Intermediate-Risk Jones, NEJM 365:107, 20114 months of Lupron and Flutamide with radiation vs. radiation alone:Cancer death at 10 years: 4% vs. 8% 13
    14. 14. TIP with Radiation: High-Risk1. 4 months Zoladex/Flutamide vs. none (Pilepich, IJROBP 50:1243, 2001)  Cancer death @ 8 years: 23% vs. 31%2. 36 months of Zoladex vs. none (Bolla, Lancet 2010)  Cancer death @ 10 years: 10% vs. 30%3. 24 months of Zoladex vs. 4 months of Zoladex plus Flutamide: (Horwitz, JCO 26:2497, 2008)  Cancer death @ 10 years: 11% vs. 16% 14
    15. 15. Observations: TIP Plus RadiationLong TIP is better than Short TIPShort TIP is better than no TIPTIP improves mortality rates to a smaller degree in Intermediate-Risk as compared to High-RiskAll the TIP/radiation studies cited used low-dose radiation compared to modern standards. Therefore, some experts contend that with modern radiation TIP’s favorable impact on survival may be less 15
    16. 16. TIP to Prolong Life with Surgery: High-Risk or Positive NodesTwo years of TIP consisting of Zoladex plus Casodex resulted in surprisingly low relapse rate in 481 men with High-Risk disease (Dorff, JCO 29:2040, 2011) 7.5% relapse rate @ five years (no control arm)Lifelong TIP is better than TIP at relapse with positive nodes after surgery (Messing, NEJM, 341:1781, 1999) Less overall mortality @ 7 years: 15% vs. 40% 16
    17. 17. TIP with Radiation for PSA Relapse Shipley, IJROBP 78:S27, 2010771 patients with positive margins or PSA relapse after surgery treated with radiation alone or radiation plus Casodex 150 mg daily for 2 yearsOnly difference in side effects was breast growthOutcome after seven years: Radiation Radiation & Casodex PSA Failure 60% 43% Metastases 12.6% 7.4% Overall Survival 86% 91% 17
    18. 18. Intermediate-Risk PSA-Relapse Advanced-Disease 18
    19. 19. TIP as Standalone Therapy Intermediate-RiskFifteen percent of men in the United States with newly- diagnosed prostate cancer are treated solely with primary TIP (Cooperberg, JCO 28:1117, 2010)Men with Intermediate-Risk and men with large prostate glands are much more likely to to maintain long-term remissions when TIP is stopped than men who are High-Risk (Scholz, Clin. GU Cancer 9:89, 2011)High-Risk men receiving TIP without surgery or XRT may have increased mortality compared to men who have surgery or XRT added to TIP (Solberg, IJROBP 80:55, 2011) 19
    20. 20. As Standalone Therapy: PSA RelapseTime to androgen independence is the same with Intermittent TIP and continuous TIP (Klotz, next slide)Quality of life is better with intermittent TIPMen on intermittent TIP have longer holiday periods when TIP is stopped if they take Proscar or Avodart (Scholz, J. Urol 175:1673, 2006) 20
    21. 21. Intermittent TIP Klotz, ASCO 2011, abstract #4514Phase III: 1386 men with PSA-relapsed disease: 690 men intermittent, 696 men on continuous 8 months TIP, restarting TIP triggered when PSA=10.Results: No difference in overall survival IHB: on treatment only 27% of the time Time to hormone resistance: 10 years More men died of non-cancerous causes 21
    22. 22. TIP as Standalone Therapy in Elderly Men with Advanced Disease that is Hormone Sensitive: Studer, JCO 24:1868, 2006985 patients median age 73 median PSA 16 randomized between immediate vs. delayed TIP (LHRH alone) Median time to TIP in delayed group was 7 years Median PSA was 56 when in delayed group when TIP was begunEarly TIP reduced prostate cancer mortality, but it was not statistically significantTIP reduced cardiovascular mortality to a statistically significant degree 22
    23. 23. TIP as Standalone Therapy in Hormone Sensitive Advanced DiseaseCasodex vs. Orchiectomy (Iverson, Scand J. Urol 30:93, 1995) 376 men, 2/3 with more than five mets. or super-scan Median survival for orchiectomy was 27 months Median survival of low-dose Casodex was 19 monthsNilutamide plus Orch. vs. Orch. (Dijkman, J. Urol 158:160, 1997) 457 men with D2 disease Median survival for orchiectomy was 30 months Median survival for Nilutamide plus Orch. was 37 mo. 23
    24. 24. Intermittent TIP Advanced Disease Salonen, J. Urol 187:2074, 2012Phase III: 852 men locally advanced or metastatic:  Randomized if PSA < 10 after 6 months of Zoladex 274 men intermittent, 280 men continuous Restart Zoladex if PSA rose to 20 (or to baseline if lower)Results: No difference in overall survival 24
    25. 25. Anti-Androgen MonotherapyLess efficacious than Lupron Shorter off-cycle when used intermittently Higher PSA nadir than Lupron Shorter survival with advanced metastatic diseaseMilder side effects than Lupron Less loss of libido and less erectile dysfunction Does not cause osteoporosis (increases estrogen)Indicated in select situations: To reduce prostate size before radiation Elderly men with less aggressive disease 25
    26. 26. Zytiga Nilutamide Ketoconazole 26
    27. 27. Zytiga for Advanced Disease de Bono, NEJM 364:1995, 2011Randomized study evaluating men with metastatic disease previously treated with TaxotereAfter one year of therapy: Placebo Zytiga PSA Response 6% 29% PSA Progression 6.6 months 10.2 months Survival 10.9 months 14.8 monthsSide Effects: Generally well tolerated. Occasional liver problems, some drug interactions 27
    28. 28. 50% PSA Decline with NilutamideResults after failure of Lupron alone: 72% responded (Nakabayashi, BJU 96:783, 2005)Results after failure of Lupron & Casodex: 33% responded (Nakabayashi, BJU 96:783, 2005) 29% responded (Kassouf, J.Urol 169:1742, 2002) 50% responded (Desai, Urology 58:1016, 2001)Potential side effects Slow light adaptation 1% incidence of interstitial pneumonitis 28
    29. 29. Ketoconazole for Men Resistant to Lupron and Casodex Scholz, J. Urol 173:1947, 200578 patients with a median PSA of 25; 53 bone scan (+)Response Rates: Average response time was 14.5 months Survival was 5 years with > 75% decrease in PSA Survival was 2 years with < 75% decrease in PSACommon side effects: Fatigue and weakness Stomach and liver problems Multiple potential drug interactions 29
    30. 30. Second Line TIPZytiga is clearly superior to the other second line agents. It is both better tolerated and more effective. If Zytiga can be obtained, it should be started firstKetoconazole has the same mechanism of action as Zytiga so Keto, being a weaker drug, is unlikely to be effective in Zytiga resistant patients. Keto is more toxic and less effective than Zytiga so it is only indicated when Zytiga is unattainable.Nilutamide is less potent than Zytiga but blocks testosterone by a different mechanism. Studies need to be done to see if there is any benefit in adding Nilutamide to Zytiga when Zytiga stops working 30
    31. 31. 31
    32. 32. Side Effects Associated with ADTBone Effects Metabolic effects Arthritis symptoms Anemia Osteoporosis FatigueSexual/Hormonal effects: Depression Low Libido Memory problems Erectile dysfunction (Mulhall) Blood sugar elevation Penile atrophy (Mulhall) Heart Issues Breast growth Increased heart risk? Hot flashes Mood Swings 32
    33. 33. Arthritis Osteoporosis Fractures 33
    34. 34. Arthritis Symptoms are Common,Particularly in the Hands and SpineCommon anti-inflammatory medications are effective Celebrex: Has an anticancer effect also (Pruthi, BJU 93:275, 2004) Motrin, Advil, Ibuprofin are short acting (3-6 hours) Aleve, Naprosyn are long acting (8-12 hours)Potential side effects include: Stomach ulcers Reversible reduction in kidney function (increased creatinine noted on blood test)Arthritis from TIP improves after TIP is stopped and normal testosterone is restored (Intermittent Therapy) 34
    35. 35. Osteoporosis and Fractures Smith, Cancer 93:789,200333% of all hip fractures are in men. Mortality is highQCT is more sensitive than DEXA for measuring densityMedian time from starting TIP to any fracture is 22 months.After 5 years of TIP, 38% of untreated men will have developed a bone fracture (mostly spine) 35
    36. 36. Preventing Bone Fractures in Men Taking TIPCalcium 1200mg/day Evening administration increases effectivenessVitamin D 1000 IU/day Need to check blood levels after 3 monthsBisphosphonates Oral: Fosamax, Actonel, Boniva Intravenous: Aredia, ZometaDenosumab: Xgeva and Prolia Monthly dosing delays bone mets (Smith, Lancet 2011) 36
    37. 37. Change in Bone Density while on TIP:Treatment Outcome Relative to Placebo Treatment Difference in Reference Bone DensityFosamax 70 mg +5.1% after Greenspan, Ann. Int. Med. weekly 1 year 146:416, 2007Zometa 4 mg IV +7.8% after Smith J. Urol 169:2008, 2003 Q 3 mo. 1 yearProlia 60 mg IM + 4.7% after Smith, NEJM 361:745, 2009 Q 6 months 1 year 37
    38. 38. Side Effects of Bone MedicationsBrief chills and muscle aches (with non-oral agents) More common during 1st treatment; less thereafter Decadron administration sharply curtails chills and achesStomach and esophageal ulcers Only with oral medicationsOsteonecrosis of the jaw Closely associated with bigger lifetime dosage of the non-oral agents Slowly reverses when treatment is stopped 38
    39. 39. Low Libido Breast growth Hot flashes Mood Swings 39
    40. 40. Loss of LibidoLoss of libido with Lupron is age dependent: Over age 70: 90% of men, over 60: 80%, over 50: 70%Casodex alone: about 50% “Hey, feet off the table please.”Proscar/Avodart: 20%Men can still perform with Viagra (Scholz, J. Urol 161:1914, 1999)Regular Cialis should be administered to prevent erectile atrophy (Mulhall) 40
    41. 41. Breast Tenderness and EnlargementMuch more common with anti-androgen monotherapyEnlargement is preventable, but not reversible! Tamoxifen: Inexpensive and effective but estrogenic activity suggests a blood clot risk (Staiman, Urology 50:929, 1997) Aromitase inhibitors: Lower estrogen, so no risk of clots Femara  (Smith, Cancer 95:1864, 2002) Arimidex  (Santen, Cancer 92:2095, 2001)Prophylactic radiation(Widmark, Urology 61:145, 2003) 41
    42. 42. Hot FlashesDepo-Provera® shot 400 mg 91% improved; 46% total resolution (Langenstoer, J. Urol 174-642, 2005)Vivelle Dot® 0.1 mg estrogen patch 83% improved; 42% had breast swelling (Gerber Urology 55:97 2000)Effexor® 12.5 mg twice a day (Quella, J. Urol 162:98, 1999) 63% of men had more than 50% decrease in hot flashesAcupuncture 30’ twice weekly for two weeks then weekly for ten weeks (Frisk, E. Urol 55:156, 2009) 78% of men improved; benefit maintained for 9 months 42
    43. 43. Mood SwingsNormally, testosterone dampens emotional response in menLow testosterone can cause: Moodiness, Depression & Anger Sadness & Crying Euphoria & JoyMen’s reaction to their increased emotionality varies For men who feel out of control or are depressed, small doses of Zoloft, Effexor, Celexa etc. are very effective 43
    44. 44. Anemia Fatigue Depression Memory Blood sugar 44
    45. 45. Anemia: Low Red Blood CellsSymptoms: Fatigue, short of breath, fast heart rateLab: Low hemoglobin (Hgb. < 10)Potential Causes: Low testosterone Cancer invading marrow Chemotherapy RadiationDiagnosis & Treatment: Check B12, thyroid and iron levels* Subcutaneous injection of Aranesp, Procrit or Epogen Blood transfusion *Iron is rarely of value and may be deleterious 45
    46. 46. Fatigue and LassitudeNarcolepsy medications Provigil & NuvigilCortisone Prednisone, DecadronAmphetamines Ritalin 10 mg AM & 5 mg @ lunch (Rozans, JCO 20:335, 2002)General supportive measures Treat anemia Fitness training 46
    47. 47. Situational or Hormonally Induced Depression May Respond to MedicationCommon antidepressants are safe enough to be prescribed by a family doctor or an oncologistIf mood fails to improve within 30-60 days consider consultation with a psychiatrist as new agents and combinations of agents may be more effectiveCommonly prescribed antidepressants are: Celexa, Zoloft, Lexapro, Effexor, Cymbalta, Paxil, Wellbutrin and Prozac 47
    48. 48. Mental Testing of Cognitive Effects Compared to Healthy Normal PeopleCombination TIP (Higano, J. Urol 170:188, 2003) Decreased spatial ability; improved verbal memoryLupron vs. Climera® patches (Beer, J. Urol 175:130, 2006) Lupron decreased immediate and delayed verbal memory compared to controls. Mental function was slowed Estrogen patches improved verbal memory performanceVarious Types of TIP for 1.8 years (Joly, J. Urol 176:2443, 2006) Lower energy, worse bladder control, less sexual function Results of cognitive testing and patient-reported mental function were similar to controls 48
    49. 49. Metformin Lowers Insulin TIP is associated with weight gain, fat accumulation and increased insulin (Basaria, Cancer 106:581, 2006) Elevated insulin associated with increased risk of prostate cancer recurrence (Lehrer, The Prostate 50:1, 2002) Diabetics taking Metfomin are 44% less likely to be diagnosed with prostate cancer (Wright, Cancer Cause Control 20:1617,2009) 49
    50. 50. Increased Heart Attacks? 50
    51. 51. Some Retrospective Studies Have Implicated TIP as Exacerbating Heart DiseaseCertainly TIP is associated with weight gain and weight gain can lead to insulin resistance and accelerated atherosclerosis.However, retrospective trials evaluating cardiovascular events have problems:  TIP is often selected for weaker, more feeble men  TIP prolongs life placing men at risk for cardiovascular events for a longer period of timeAdditionally, there are some reasons to consider that lower testosterone would improve survival  Women outlive men by an average of 4 years  Also, recall the results of the randomized Studer trial (slide #22) that showed reduced cardiovascular mortality 51
    52. 52. What About Testosterone Causing Heart Problems? Basaria, NEJM 363:109, 2010Trial Design:  209 men mean age 74 and testosterone averaging 243 were randomized to testosterone gel vs. placebo  Many had previous HTN, diabetes, obesity and high cholesterolResults:  With treatment, testosterone increased to 574 in the treated men  Higher testosterone did improve strength and energy levels  Hemoglobin levels increased in the testosterone groupUnanticipated Toxicity:  Within 6 months of starting the trial 9 men in the testo group had serious cardiovascular events: 3 heart attacks, 3 hospitalizations for chest pain or heart failure, two men with fainting spells and one stroke. The trial was stopped early  In the placebo group only one man suffered a fainting spell 52
    53. 53. Meta-Analysis: TIP and Heart Disease The Final Word on this Hot Topic! Nguyen, JAMA 306:2359, 2011Analysis of 4100 patients evaluated in 8 randomized prospective trials comparing men receiving TIP vs. those not receiving TIP Cardiovascular mortality was found to be equivalent in both groups Prostate cancer specific and overall mortality was reduced in the groups receiving TIPPractically every published study implicating TIP as a possible cause for heart disease is retrospective 53
    54. 54. TIP and Heart Disease The Pros and the Cons:The “Con” Men who are overweight are prone to insulin resistance, higher blood sugar levels should think twice before starting TIPThe “Pro” Men on TIP develop a mild anemia, i.e., lower hemoglobin levels. This puts less strain on the heart and slightly lowers the risk of heart attacks and strokesBottom Line, “Whether taking TIP or not—Keep your weight under control!” 54
    55. 55. ConclusionsTestosterone blockade has powerful anti-cancer effectsTreatment with TIP needs to be individualized:  Insufficient treatment of men with High-Risk can lead to increased mortality from prostate cancer Over-aggressive treatment in Low or Intermediate-Risk incurs unnecessary side effects without prolonging lifeMechanisms for reducing side effects include: Intermittent therapy Anti-androgen monotherapy Supportive medications, diet and exerciseMen taking TIP who have major heart problems and are overweight are probably chancing an exacerbation of their heart problems 55