Successful Approaches in PC München, Germany Stephen B. Strum, MD, FACP Erfolgreiche Konzepte im Kampf gegen den Prostatakrebs

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The most important principle in all life systems!

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The Dynamics of Putting Concepts Together into Strategy 8

Subject: [P2P] Radiation therapy Date: April 16, :12:55 AM PDT To: Ed Domanskis, age 64,DX 6/16/08,bPSA 1.3, Biopsy 6/16/08,10 cores, GS 8 (Bostwick Lab), Bone Scan Negative; RP 8/4/08, GS7, Extracapsular extension +, SVI No,pN0, Perineural invasion +, US-PSA 0.01 (12/11/08), 0.21 (3/1/09), (4/6/09). I am looking at adjuvant/salvage radiation therapy. I would like to know if tomotherapy, IMRT would be best. I have read about 4D-IG IMART with DART as well as RapidArc. Thanks! Applying the Concepts

1. No mention of PSA history prior to RP to determine PSA doubling time. 2. No mention of PAP, CGA, CEA, NSE to evaluate nature of PC given GS (4,4) 3. No mention of clinical stage or calculated nomograms or neural net data 4. No apparent expert review of GS from RP or use of ploidy analysis or IHC (Immunohistochemistry) 5. Calculated PSAV is GS 7 (not validated) results in prediction of 38% for local recurrence versus 62% for distant disease. 6. Patient is focused on “what to do” rather then understanding nature & extent of PC Points Made in my Response

Active Objectified Surveillance & Other Strategies

Active Objectified Surveillance Patients with “insignificant” PC based on set clinical & pathological criteria Patients with significant age & co-morbidity factors Patients able to be monitored over time Determine thresholds relating to treatment intervention Patients who are reclassified as higher risk can be treated with cure Reduce psychological stress of living with untreated cancer

“Insignificant” Prostate Cancer Gleason score 6 or less PSA 10 or less Clinical stage T2a or less Free to total PSA percent > 15% Less than 3 cores involved 50% or less of any one core with PC PSA doubling time > 3 years

AOS (active objectified surveillance): Key Role of Status

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Importance of Milieu in PC Behavior A Key Ingredient in any Active Surveillance Strategy

Klotz L: Active surveillance with selective delayed intervention is the way to manage 'good-risk' prostate cancer. Nat Clin Pract Urol 2:136-42; Study begun in 1995 involving 299 patients 2.Median PSADT 7 yrs with 42% having DT > 10 yrs 3.At 8 yrs, overall actuarial survival 85% with PC- specific survival of 99% Key Findings

Optimal ADT (androgen deprivation therapy)

6 Ways to Optimize ADT 1. Block androgen access to the PC cell 2. Ensure significant lowering of Testosterone 3. Measure testosterone using accurate lab assay 4. Use US-PSA as biologic endpoint for ADT 5. Use measures that down-regulate (dR) sensitivity of the androgen receptor (AR) 6. Block bone-derived growth factors that are released due to excessive osteoclast activity (induced by androgen deprivation)

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Are We Using the Optima Dose of Dutasteride ? Dr. Mostaghel's group looked for gene changes in 75 men with localized PC. Twenty-five had RP alone, 26 were given neoadjuvant dutasteride at 0.5 mg, and the remaining 24 received dutasteride, 3.5 mg orally per day for 4 months prior to RP.

ADT is about Androgen Availability Huggins won Nobel Prize 43 years ago showing PC dependence on Androgens. Testosterone assays inaccurate at low T levels: need to use LC/MS/MS based assays. PC growth is mediated by androgens. We call it Androgen Dependent PC (ADPC) or Androgen Independent PC (AIPC) or Castration Resistant PC (CRPC) but PC growth is androgen related. PC mets even synthesize their own androgens. Testosterone level (T) is a key Biological End Point. T not measured in 95% of men with PC. “Castration” threshold should be < 20 ng/dl. Further lowering of T may enhance response.

 Lowest T level with impact on survival was 32 ng/dl.  Mean survival, free of developing AIPC, in men with breakthrough increases in T > 32 ng/dl was 88 months (CI mos).  Mean survival in men with T 32 ng/dl was 137 mos (CI ).  In men with breakthrough increases > 50 ng/dl, those men with maximal ADT had a significantly longer survival free of AIPC. < > 50

Importance of US-PSA (ultra- sensitive) to Monitor ADT PSA nadir > 0.05 highly correlated with shorter time to progressive PC & prostate cancer-specific survival.

The achievement of a PSA nadir of 0.05 or less was the most significant endpoint insofar as time to progressive PC and PC mortality.

Androgen Receptor (AR) Related Dysfunction (1) Reduce AR sensitivity Prolactin Inhibitors 5AR inhibitors EGCG HSP inhibitors PPAR-G ligands DIM & POMx Silymarin Melatonin (2) Avoid Drugs Stimulating “Promiscuous” AR Avoid or use cautiously standard glucocorticoids such as prednisone & dexamethasone Use triamcinolone instead e.g. HDK with triamcinolone instead of Hydrocortisone (HC)

Androgen Receptor (AR) Related Dysfunction (3) Evaluate for ARM (androgen receptor mutation)– see cancer.org/education/andeprv/Strum_IADT.htmlhttp:// cancer.org/education/andeprv/Strum_IADT.html Withdraw anti-androgen, progestin, estrogen to see if PSA or other marker is reduced. If possible ARM due to Casodex need 6 weeks to eliminate Casodex (bicalutamide) from body. (4) Avoid agents that stimulate ARM Steroidal anti-androgens such as CPA (cyproterone acetate) Progestins, in certain contexts.

Androgen Deprivation Therapy (ADT) Immediately Induces Bone Resorption Surgical Orchiectomy LH-RH agonists like Zoladex, Lupron GnRH antagonists like Degarelix Anti-Androgens like bicalutamide, eulexin Ketoconazole Estrogens Androgen Receptor Antagonists Goal Block bone-derived growth factors released due to ADT effect on bone resorption.

CLARKE NW, MCCLURE J, GEORGE NJR: THE EFFECTS OF ORCHIDECTOMY ON SKELETAL METABOLISM IN METASTATIC PROSTATE CANCER. SCAND J UROL NEPHROL 27: ,  This is NOT new information but we continue to neglect this downside of ADT.  We should be preventatively blocking bone resorption prior to starting ADT.  This may improve (likely) the natural history of men with PC, as well as other malignancies that metastasize to bone.  This is NOT new information but we continue to neglect this downside of ADT.  We should be preventatively blocking bone resorption prior to starting ADT.  This may improve (likely) the natural history of men with PC, as well as other malignancies that metastasize to bone.

Testosterone (T) Inhibits Osteoclast Activation. T normally inhibits PTH (parathormone). PTH causes bone loss by activating osteoclasts. ADT lowers T and osteoclast inhibition lost and bone loss occurs. Chen Q, Kaji H, Sugimoto T, et al: Testosterone inhibits osteoclast formation stimulated by parathyroid hormone through androgen receptor. FEBS Lett 491:91- 3, 2001.

All of Biology is a Two Edged Sword Part of optimizing ADT is recognition of the above statement. We need to start therapies to minimize the down- sides of any treatment we use, including ADT. A key focus should be to prevent osteoclast activation with release of bone-derived growth factors. Agents like bisphoshonates & Denosumab should be used early in the treatment of men with PC.

Monoclonal antibody to Receptor Activator of Nuclear Kappa Ligand (RANKL) Stops Bone Resorption & Decreases Skeletal-Related Events Better then Aredia or Zometa. 35

When we decrease the side-effects of any treatment, we improve the therapeutic index (TI) Treatment Benefits Treatment Side Effects = TI cancer.org/resource/pdf/I s2-1.pdf

CRPC still not good term: No agreed upon castration level Hypersensitivity of AR AR mutation Promiscuous AR PC mets synthesize androgens Level 1: PSA serially rising Testosterone < 20 ng/dl ARM excluded Level 3: Estrogen given Estradiol blood levels checked Rxs to prevent side-effects Level 2: HDK given (properly) Keto blood levels High-dose Keto given AIPC or CRPC

When to Start Chemo ? Progressive PC on ADT ADT3 or ADT4 used HDK given Estrogen Rx given No chance for salvage RP, RT or Cryo Other Rx options used Vaccine AR antagonist Clinical trial No serious patient co- morbidities present Heart disease Kidney disease Bone marrow suppression More …

When to Start Chemo ? Aggressive PC needing more intense Rx Neuroendocrine PC or other aggressive features, perhaps detected by gene expression signatures may require early chemo or chemo-hormonal therapy. See the very first issue of Insights at Expertise in administration of chemo exists and patient context indicates need

Taxotere: High or Low Dose ? I prefer weekly Taxotere regimens at a lower dose (30 mg/m 2 ) then every 3 week regimens at a higher dose (75 mg/m 2 ). Patient tolerance & quality of life is far better with weekly regimen. Complaints of severe fatigue are less. Pre-meds used with every 3 week do not need to be used with weekly (perhaps very low dose steroid in first few weeks). Survival data in (TAX 327) randomized trial better for every 3 week Taxotere, but difference involved weeks: median survivals 18.9 mos versus 17.4 mos. Patients, even older men in 70’s or greater, able to tolerate weekly chemo far better then every 3 wk Rx. Lowering of WBC greater for every 3 wk regimen vs weekly regimen.