Treatment of Advanced Prostate Cancer
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1 Treatment of Advanced Prostate Cancer Wm. Kevin Kelly, DO Associate Professor of Medicine and Surgery Yale University Yale University School of Medicine
2 Advanced Prostate Cancer Metastatic Cancer Prostate Rising PSA Locally Advanced Prostate Cancer
3 Rising PSA after radical prostatectomy and radiation therapy
4 A. Rising PSA after radical prostatectomy and radiation therapy 4 3 PSA (Prostate Spec Antigen), Blood (ng/ml) PSA (Prostate Spec Antigen), Blood H ng/ml Apr Jul Oct Jan 2009 Apr Jul Oct TENNEY, JAMES B. ng/ml PSA (Prostate Spec Antigen), Blood (ng/ml) PSA (Prostate Spec Antigen), Blood H CHALKER, BURTON C. ng/ml PSA (Prostate Spec Antigen), Blood (ng/ml) PSA (Prostate Spec Antigen), Blood H Jan 2009 Apr Jul Oct MORAN, JOHN J
5 PSA doubling time or PSA slope s/nomograms/prostate/psadoubli ngtime.aspx
6 Rising PSA after radical prostatectomy and radiation therapy Treatment Options Radiation therapy to prostate bed Dietary changes Hormone therapy Experimental therapy Immunotherapy Vaccines Differentiation therapies Novel Anti-androgens Cytotoxic chemotherapy
7 Rising PSA and Risk of Developing Metastatic Disease after Surgery Gleason score > 7 7 Time to PSA relapse 3 yrs > 3 yrs 3 yrs > 3 yrs PSADT (month) <3 3 to 9 9 to <3 3 to 9 9 to < 3 3 to 9 9 to < 3 3 to 9 9 to Time to Mets (years) > > Antonarakis et al.; ASCO 2009: Abstract #5008
8
9 Dietary Intervention After Radical Prostatectomy
10 Recommendations for observation and dietary intervention Good for Low risk patients Healthy lifestyle Need to be cautious not to overdue supplements Good source of Dietary information: Change strategy if PSA DT increases
11 Phase II study of Pomegranate juice for men with rising PSA following surgery or radiation therapy 12% decrease in cell proliferation (p=0.0048) 17% decrease in apoptosis (p=0.0004) Pantuck, A. J. et al. Clin Cancer Res 2006;12:
12 Phase II Study of Pomegranate Juice for Men with Rising Prostate-Specific Antigen following Surgery or Radiation for Prostate Cancer Pantuck A J et al. Clin Cancer Res 2006;12:
13 Systemic Treatment Options for Patients with PSA failure Observation with dietary modifications Investigational therapies Vaccines Hormone Therapy (decrease male hormone testosterone) LHRH analogs (Luprolide, Goserlin acetate) Combined Androgen Blockade Intermittent therapy Potency spearing therapy
14 Hormone Therapy in Men with Prostate Cancer
15 Hypothalamus CRH GnRH DES Treatment GnRH Analogs Leuprolide Goserelin Abarelix Centorelix Orgalutran Prostate Cancer Cell Protein Synthesis Pituitary ACTH Adrenal Glands FSH LH Total Androgen Blockade Anti-Androgens Flutamide Bicalutamide Nilutamide AR Androstenedione DHEAS DHEA Testosterone Estradiol Testes Androstenedione Testosterone (T) Estradiol Surgical Orchiectomy SHBG T T DHT 5 alpha reductase Finasteride Dutesteride
16 Response Following Hormonal Therapy 1. Symptoms: Palliation 2. PSA: 61-74% normalize (<4 ng/ml) 3. Measurable disease: 30-50% regress, most stable 4. Bone Scan: Only 30-50% improve Hormonal Therapy typically lasts an average of months but may work for over 10 years in some patients
17 Hormonal Therapy: Side Effects Impotency Anemia Muscle wasting Weight gain Osteoporosis Increased lipids Increased cardiac disease
18 Bone Loss- Osteopenia or Osteoporosis with hormone therapy Percent change Total hip P= Time (mo) Prevention: Calcium + Vitamin D Avoid Alcohol Avoid Smoking Exercise (weight bearing) Medications Pamidronate Zolendronic Acid
19 Intermittent Hormone Therapy
20 Intermittent Androgen Deprivation Therapy S9346 (INT- 0162) study schema Hussain, M. et al. J Clin Oncol; 24:
21 Overall survival by prostate-specific antigen (PSA, ng/ml) status at end of induction Hussain, M. et al. J Clin Oncol; 24:
22 ADT months
23 Second-Line Hormonal Therapies Anti-androgen withdrawal Bicalutamide Flutamide Nilutamide DES Ketoconazole
24 Chemotherapy in Prostate Cancer: Historical Perspective Pre-1990 s clinical trials between low response proportion (< 10%) no impact on survival does chemotherapy have a role?
25 Docetaxel Chemotherapy: Microtubules Dynamics as a Target of Cancer Therapy Microtubules G2 Vinblastine Docetaxel Paclitaxel Depolymerization S Mitosis Microtubule Stabilizer Microtubule Dynamics Polymerization Cell Death G1
26 Prostate Cancer Treatment Paradigms: Chemotherapy Works!! Clinically localized Relapsed and newly diagnosed M+ Hormone refractory Local treatment Endocrine Docetaxel-based regimens Improves survival
27 Expanding the Role of Chemotherapy in the Treatment of Prostate Cancer Adjuvant HRPC, nonmetastatic Neoadjuvant PSA relapse HRPC, metastatic, first line Second-line options Prostate Cancer Treatment Continuum Currently used Trials ongoing Endpoint selection: survival, time to progression vs palliative
28 Class of agent Novel Agents in CRPC Agent 17 hydrolase/17, 20 lyase inhibitor Abiraterone Anti-angiogenic/immunomodulatory CC4047,Lenalidomide, thalidomide Anti-CTLA4 antibody Ipilimumab Anti-Il-6 antibody CNTO 95 Anti-insulin-like GFR antibody IMC-A12 Anti-integrin anti-body CNTO 95 Anti-PSMA immunoconjugate MLN2704, 177 Lu-J591 Anti-prostate stem cell antibody AGS-PSCA Anti-VEGF Bevacizumab Cytotoxic agent ABT-751, abraxane, E7389, GMO-paclitaxel, Irofulven, Paclitaxel poliglumex, Pemtrexed, Trabectin, Vinfluvine, Epothilones, Satraplatin EGFR antibodies\tki Pertuzumab, Cetuximab, Erlotinib, Gefitnib, Lapatinib GMP phospodiesterase inhibitor Exisulind HSP-90 inhibitor 17-AAG HDACi LBH589, Romidepsin, Valproic acid, Vorinostat, Belinostat Integrin receptor antagonist Cilengitide M-TOR inhibitor RAD-001 Multi-targeted TKI Sunitinib, Sorafenib, CEP 701 Pro-apoptotic agent AT-101 Proteosome Inhibitor Bortezomib Signal Transduction inhibitor PCK-3145 Survivin suppressant YM155
29 Thank You
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31
32 Prostate Cancer Death Prostate Cancer: Growth Rate and Progression Metastatic Disease Localized Disease Cancer Progression Early Detection Onset of Cancer Life Expectancy Natural Death
33
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