Themen der Veranstaltung in DARMSTADT

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Themen der Veranstaltung in DARMSTADT

• Algorithmen
• Gleason Score
• Optimierte ADT
• Androgenentzugs -syndrom
• Zeichen des AUPK
• Wann Chemotherapie
• High vs Low doseTaxotere
• Andere Medikamente
• Falldiskussionen

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KEY CONCEPTS
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GLEASON SCORE (GS) ALGORITHMS

• GS Integral Part of All Risk Assessment Tools
• Patient Status is Endpoint for these Tools
• Nomograms, ANN (Artificial Neural Nets) are
  involved at all stages of PC (prevention to end
  of life)
• GS relates to Nature of PC
• PSA less reliable as GS gets higher (8 to 10)
• Need to check other Biomarkers with GS 8-10 such
  as CEA, CGA, NSE, PAP. See page 64 in Primer.

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Moving Concepts into Strategy

• This is the thought flow that is critical in any
  assessment of a living entity.
• It is the key to obtaining successful outcomes.

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Optimal ADT (androgen deprivation therapy)
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6 Ways to Optimize ADT

• Block androgen access to the PC cell
• Ensure significant lowering of Testosterone
• Measure testosterone using accurate lab assay
• Use US-PSA as biologic endpoint for ADT
• Use measures that down-regulate (dR) sensitivity
  of the androgen receptor (AR)
• 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.
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ADT is about Androgen Availability

• 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 lt 20 ng/dl.
• Further lowering of T may enhance response.

• 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.

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• Lowest T level with impact on survival was 32
  ng/dl.
• Mean survival, free of developing AIPC, in men
  with breakthrough increases in T gt 32 ng/dl was
  88 months (CI 55-121 mos).
• Mean survival in men with T lt 20 ng/dl and no
  breakthrough increases gt 32 ng/dl was 137 mos (CI
  104-170).
• In men with breakthrough increases gt 50 ng/dl,
  those men with maximal ADT had a significantly
  longer survival free of AIPC.

lt20
20-50
gt 50
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Importance of US-PSA (ultra-sensitive) to
Monitor ADT

• PSA nadir gt 0.05 highly correlated with shorter
  time to progressive PC prostate cancer-specific
  survival.

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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.
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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)

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Androgen Receptor (AR) Related Dysfunction

• (3) Evaluate for ARM (androgen receptor
  mutation) see http//www.prostate-cancer.org/edu
  cation/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.

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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.
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Clarke NW, McClure J, George NJR The effects of
orchidectomy on skeletal metabolism in metastatic
prostate cancer. Scand J Urol Nephrol 27
475-483, 1993.

• 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.

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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 49191-3, 2001.
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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.

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Monoclonal antibody to Receptor Activator of
Nuclear Kappa Ligand (RANKL) Stops Bone
Resorption Decreases Skeletal-Related Events
Better then Aredia or Zometa.
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When we decrease the side-effects of any
treatment, we improve the therapeutic index (TI)
Treatment Benefits Treatment Side Effects
TI
http//www.prostate-cancer.org/resource/pdf/Is2-1
.pdf
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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
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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
  http//prostate-cancer.org/resource/pdf/Is1-1.pdf.
  

• Expertise in administration of chemo exists and
  patient context indicates need

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Taxotere High or Low Dose ?

• I prefer weekly Taxotere regimens at a lower
  dose (30 mg/m2) then every 3 week regimens at a
  higher dose (75 mg/m2).
• 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 70s 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.

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Alternative Medikamente

• HDK triamcinolone
• Insights 2001
• Keto blood levels with goal of at least 3.0
• Monitor liver function
• Estrogens
• You have access to Estradurin which has good
  published results
• End Point E2 level of at least 1,000 pg/ml

• GM-CSF combos
• Combine with retinoid acid
• Combine with Thalidomide or Revlimid
• Use alone as per Small et al
• PPAR-gamma agonists
• Low dose (7.5mg/d) Actos
• Combine with HDAC inhibitor like Valproic acid or
  COX-2 inhibitor like Celebrex
• Memantine NMDA receptors on PC cells
• Celebrex Dostinex combination

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Thank you for your attention.