Guiding Patients on the Safe & Effective Use of Science-Based Nutraceuticals Aaron E. Katz, MD Associate Professor of Clinical Urology Director, Center of Holistic Urology Columbia University Medical Center Center for Holistic Urology Columbia University Established 1998 Perform basic science investigations Develop translational human clinical trials Single Center Multi-Center Placebo controlled Phase 3 Educate patients and physicians Generate manuscripts in peer-reviewed journals www.holisticurology.columbia.edu Center for Holistic Urology Columbia University Practitioners Aaron E. Katz, MD (Urologist) Debra Bemis, Ph.D (Scientist) Jillian Capodice, LaC (Acupuncturist) Geovanni Espinosa, ND (Naturopathic Physician) Jun Yan, PhD (scientist) Current Clinical Trials 9 9 9 9 9 9 Prostate Cancer Prevention: Prostate Cancer Treatment: Prostate Cancer Recurrence: Bladder cancer prevention: Hot Flashes: Pelvic pain 2 1 1 1 1 1 Why Investigate CAM? Patient driven Not all conventional therapies 100% effective Supposedly non-toxic Many tumors are not organ-confined: Holistic Approach What to Look for in Natural Therapies • A known mechanism of action • Evidence that it relieves symptoms • Demonstrated safety • Quality of Product • Low cost • No interaction with other meds Plant-Derived Anticancer Drugs 1881 1958 1959 1960 Podophyllum Catharanthus roseus Ochrosia elliptica Podophyllotoxin Vincristine & Vinblastine Ellipticine 1997 Taxus brevifolia Paclitaxel Anticancer Drugs 1966 Raphanus sativus Olomucine Roscovitine (synthetic) Camptotheca acuminata Camptothecin 1980 1989 Amoora rohituka Flavopiridol (semi-synthetic) 1972 Cephalotaxus harringtonia Combretum caffrum Combretastatin A4 Homoharringtonine Holistic Urology Roles for Supplements • • • • • • • Urinary Tract Infections BPH and Voiding Disturbances PSA elevations Pre-cancerous conditions (PIN) Prostate Cancer Bladder Cancer Sexual Dysfunction 2009 Estimated US Cancer Cases* Men 745,180 Women 692,000 Prostate 25% 26% Breast Lung & bronchus 15% 14% Lung & bronchus Colon & rectum 10% 10% Colon & rectum Urinary bladder 7% 6% Uterine corpus Non-Hodgkin lymphoma 5% 4% Non-Hodgkin lymphoma Melanoma of skin 5% 4% Thyroid Kidney & renal pelvis 4% 4% Melanoma of skin Oral cavity 3% 3% Ovary Leukemia 3% 3% Kidney & renal pelvis Pancreas All Other Sites 3% 3% 20% 23% Leukemia All Other Sites *Exclude s ba sal and squamous cell skin cancers and in situ carcinoma s except urinary bladder. Source: American Cancer Society, 2008. Target Populations for Prevention in Your Practice • Primary Prevention: • African Americans • Family History • High Grade PIN • Secondary Prevention: • Elevated PSA, Negative biopsy • Post-RRP/Radiation with Rising PSA All Men Over 40 are at Risk!! Prostate Cancer Development • Linked to Inflammation • Many men have prostatitis on biopsy • Cancers linked to Inflammation: • • • • Colon Breast Bladder Thyroid Pathway for Human Prostate Cancer Progression NORMAL EPITHELIUM PROSTATIC INTRAEPITHELIAL NEOPLASIA (PIN) INVASIVE CARCINOMA METASTASIS ANDROGEN INDEPENDENCE Pre-Cancerous Condition ImmunoKinoko AHCC 12 AHCC Production Facility (Sapporo, Japan) 13 Annual Research Symposium 14 AHCC (Active Hexose Correlated Compound) 1. Very low-molecular-weight (5,000Da), highly absorbable alphaglucan-rich compound 2. Produced from enzymatically fermented mycelium of Japanese medicinal mushrooms 3. Clinical shown to have strong immunomodulating properties • Increase NK cell activity • Increase number and activity of DC cells • Increase cytokine response 4. Research • 24 Pubmed-listed studies published in peer-reviewed journals • Numerous other studies published in Japanese journals 5. Clinical Use: in over 1,000 clinics and hospitals, primarily in Asia 1. Primary Care Clinics (immune support and prevention) 2. Cancer Clinics (immunotherapy reduction of chemo side-effects) 3. Hospitals (reduction of hospital borne-infections) 4. Hepatology Clinics (reduce viral loads in Hep-C patients) AHCC and NK Cells • Significantly increases NK cell activity in immune compromised patients • Stimulates T-cells, macrophages and increases cytokines • Increases activity and number of DC cells • Appears to be able to stimulate and modulate because it works on both the macrophages and the cytokines: valuable links and network messengers • Built in dampening system; can be taken continuously and does not need to be stopped like other immune-enhancing supplements AHCC Research: Select Published Animal Studies ▪ Infections: influenza20, west nile virus15, bird flu11, MRSA19 ▪ Tumor necrosis, improved survival of tumor-bearing mice ▪ Reduced side-effects of chemo8 & non-interaction with chemo3 ▪ Anti-inflammatory properties (colitis26; diabetes13) ▪ Auto-immunity (Amyotrophic Lateral Sclerosis (ALS)12) ▪ Protective effect on bone marrow9 , thymus gland7, liver22, spleen8) ▪ Enhanced activity of NK cells, T-cells, macrophages, cytokines AHCC: Select Published Clinical Studies ▪ 269 liver cancer patient prospective cohort study (1992-2001) showed longer “no recurrence” period and increased survival rate (Journal of Hepatology)33 ▪ 132 stomach cancer patients showed enhanced 5-yr survival rate34 ▪ 44 liver cancer patient placebo-controlled study showed prolonged survival and improved Quality of Life36 ▪ 30 healthy elderly patient study at Yale Medical School showed increased cytokine production (TNF-γ and IFN-α) 4 ▪ 20 healthy patient DBPC study showing increased number and activity of dendritic cells (Nutrition and Cancer)5 ▪ Phase-I 26-subject safety study at Faulkner Hospital (9g/day)10 TIME Feb. 23, 2004 Role of NF-kB in Development of Cancer Anti-apoptosis/survival Immortality e.g; bcl-xl, cIAP, survivin, cFLIP, TRAF, SOD, γ-GCS e.g; telomerase Inflammation Proliferation NF-κB TNF, IL-1,Che mokines Angiogenesis e.g; TNF, IL-1, IL-6 CyclinD1, cMyc Tumor promotion VEGF, TNF, IL-1, IL-8 e.g; COX2, iNOS, MMP-9, uPA Metastasis e.g; ICAM-1, VCAM-1, ELAM-1 Aggarwal BB, Cancer Cell, 2004 Zyflamend: Herbal Anti-Inflammatory Turmeric (14.1%) Holy basil (12.8%) Curcumin Ursolic acid Ocimum sanctum Curcuma longa Rosemary (19.2%) Rosmarinic acid, Camphor, Borneol, Cineol Ginger (12.8%) Gingerol Rosmarinus officinalis Zingiber officinalis Green tea (12.8%) Epigallocatechin gallate Huzhang (10.2%) Resveratrol, Thymol Camellia sinensis Polygonum cuspidatum Chinese goldthread (5.1%) Berberine Barberry (5.1%) Berberine Berberis vulgaris Coptis Chinensis Baikal skullcap (2.5%) Baicalin, Baicalein, Wogonin Scutellaria baicalensis Oregano (5.1%) Thymol Origanum vulgare Clinical Trial Administering Zyflamend™ for Prostatic Intraepithelial Neoplasia (PIN) HGPIN (+): Positive NF-kB HGPIN (-): Negative NF-kB Lycopene Found in tomatoes, watermelon, guava and even pink grapefruit ProstaCell contains this antioxidant with highest capacity for scavenging free radicals1 1 Gester. J. Amer. Coll. Nutr. 16: 109-126, 1997 Lycopene: Epidemiological Data Dietary consumption of lycopene associated with a decreased cancer risk 1 35/ 72 studies demonstrated a significant decrease in risk1 The largest study found that 2-4 servings of tomato sauce per week was associated with a reduction of 35% in the risk for CaP2 1 2 Giovannucci. J. Natl. Cancer Inst. 91:317, 1999 Barber. Prostate Cancer Pros. Dis. 5:6, 2002 Lycopene Supplementation before radical prostatectomy, 20012 - Phase II randomized clinical trial - ↓ involvement of surgical margins, ↓ extent of HGPIN as well as ↓ in tumor size 2Kucuk et al. Can. Epid. Bio. Pre. 8:861, 2001. Soy Isoflavones Properties Active metabolites: genistein and daidzein Adventist Health Study, 1998 ↓ CaP risk1 - consumption of soy milk Genistein has been shown to: - Reduce DNA synthesis in LNCaP cells - Inhibit the effect of testosterone in development of CaP in rats2 1 2 Jacobsen et al. Cancer Causes Control, 9:553, 1998. Geller et al. Prostate, 34:75, 1998. Four Important Dietary Isoflavones O H0 Formononetin O H O 0 CH 3 O Daidzein O H0 OH O Biochanin OH Genistein H O O 0 CH 3 O OH O H O Dietary Sources of Isoflavones • Legumes – plants with high protein levels • Chick peas, lentils, soy, navy beans etc • 20-50 mg per day intake in Asian, Mediterranean, African diets • 1-3 mg per day intake in Western diets GeniKinoko GCP 31 A Concentrated Aglycone Isoflavone Preparation (GCP) Demonstrates Potent Anti-Prostate Cancer Activity in vitro and in vivo Debra L. Bemis, Jillian L. Capodice, Manisha Desai, Ralph Buttyan, and Aaron E. Katz Department of Urology, College of Physicians and Surgeons and ColumbiaUniversity Medical Center, New York, New York Clinical Cancer Research, 2004 Effect of GCP on Growth of LNCaP Tumors Mouse Tumor Volumes Median Volume 250 200 150 Control Treatment 100 Prevention 50 0 0 1 2 Week 3 4 Immunohistochemical Detection of Apoptosis-TUNEL 100 * * Number of TUNEL-positive nuclei 90 LNCaP-untreated 80 70 60 50 40 30 20 10 0 *Error bars are ± SEM; p<0.001 compared to control LNCaP+ 2% GCP diet GCP + Radiation Reduces Clonogenic Survival Better than Genistein Survival, % of Control 100 80 60 40 20 0 Control 2 Gy Genistein Radiation Alone GCP Alone Gen+2Gy GCP+2 Gy Treatment of CWR22R cells “Effects of a Genistein-Rich Extract GCP on the Treatment of Prostate Cancer” Urology 63:259-63, 2004 Ralph W. deVere White Robert M. Hackman Stephanie E. Soares Laurel A. Beckett Yueju Li Buxiang Sun Individual Changes in PSA Among Men on Active Surveillance 10 8 PSA (ng/ml) 6 Baseline 4 6 months 2 0 1 2 3 4 5 6 7 8 Subject number Superficial Bladder Cancer Evaluation • Cystoscopy – Sensitivity 70% – Gold Standard For Detection – Invasive • Cytology – Sensitivity 40% and Specificity 90% – Less Sensitive for Low Grade Tumors – False (+): Inflammation, Urothelial Atypia, Radiation / Chemotherapy, Instrumentation GCP Induces Apoptosis in Bladder Cancer Cell Lines: Caspase-3 Activity After 24 hrs Exposure to GCP HT-1376 Cell Line T24 Cell Line 6 35 30 Fold Increase Over Control 4 3 2 1 25 20 15 10 5 ) m l m l nM (1 0 TP A ug / ug / 25 50 P P G C l l ug /m en is te en ist e in in 25 50 ug /m (1 0 A G G C nM ) l ug /m ug /m 25 P 0 TP ug /m l 50 GC 25 ein G CP ug /m l 50 in te ni st en is Ge G l 0 G Fold Increase Over Control 5 Role for GCP in Bladder Cancer • Prevent recurrent TCC • Delay progression of disease • Use in combination with existing intravesical agents • Delay/prevent radical surgical removal ProstaCell (Quality of Life Labs) GCP Selenium Vitamin E Lycopene Green Tea www.q-o-l.com Pomegranates and Prostate Cancer Pomegranates and Prostate Cancer Pre-Clinical Data Summary In vitro studies show: • 59-75% growth inhibition of PC3 • Delayed progression into S phase • Low levels of apoptosis In vivo studies in SCID mice show: • 52% growth inhibition of LAPC-9 tumors • 70% reduction in PSA • Prolonged survival Phase II Study for Men with Rising PSA after RRP or XRT • Men with Recurrent Prostate Cancer • Rising PSA after RRP or XRT • Low risk: PSA < 5, Gleason < 8 • No evidence of metastatic disease • No previous hormone therapy • Baseline PSA DT Interim Results: PSA Doubling Time (Year 1) Mean ± SD PSADT Before Baseline PSADT After Baseline Change 14.3 months 25 months 11 months Signed Rank Test P=0.0481 * Interim Results: PSA Doubling Time (Year 2) Mean ± SD PSADT Before Baseline PSADT After Baseline Change 14.3 ± 10.8 37.5 ± 33.5 23.2 ± 29.8 Signed Rank Test P=0.0481 * Pantuck et al PCF, AUA, 2005 “Final” Results: PSA Doubling Time (Year 3) Mean ± SD PSADT Before Baseline PSADT After Baseline Change 15.0 ± 11.1 54.0 ± 53 39.00 ± 45.6 Signed Rank Test Pantuck et al Clinical Cancer Research, 2006 P=0.0001 Phase III Study Confirmation in a Randomized Study Multi-Center Double Blind Placebo Controlled 3:1 Treatment to Control 250 patients Option to cross over to open label at progression Centralized Randomization/Data Management/CRO CAM for Prostate Cancer: Active Holistic Surveillance Low-risk prostate cancer patients Low fat diet, increase fresh vegetables Vitamin E and selenium Lycopene Soy supplementation Pomegranite juice per day 2-4 cups of green tea Zyflamend 3 tabs per day CAM and Prostate Cancer: What are the roles? Improve the health of our patients Develop prevention protocols Consider as an alternative to Watch and Wait Active Holistic Surveillance with delayed intervention Consider in prevention of High Risk Patients that have been treated Prolong PSADT in patients post therapy Acknowledgements Department of Urology, Columbia University, NY, NY Debra Bemis,Ph.D. Ralph Buttyan, Ph.D. Jillian Capodice, M.S., L.Ac. Yi Chen Cao Geovanni Espinosa, ND The Center for Holistic Urology Columbia-Presbyterian Medical Center www.holisticurology.columbia.edu