Prostate Cancer and Oxygen: Prostate Cancer and Oxygen: New - PowerPoint PPT Presentation

Prostate Cancer and Oxygen: Prostate Cancer and Oxygen: New Concepts and Therapies New Concepts and Therapies Robert Bristow MD PhD FRCPC Departments of Radiation Oncology and Medical Biophysics, University of Toronto and Ontario Cancer Institute/Princess Margaret Hospital (University Health Network) Princess Margaret Hospital University Health Network Bristow-Brampton-2009 PMH- -Terry Fox Terry Fox PMH Hypoxia Program Hypoxia Program Spatio Spatio- -Temporal Targeting Amplifying Temporal Targeting Amplifying Radiation Response Radiation Response

Prostate Cancer: Some Basics Prostate Cancer: Some Basics Risk factors : age, family history, high-fat diet, African ancestry Currently, the extent and prognosis of prostate depends on: (1) a digital rectal exam (DRE) and spread of disease (TNM) (2) the prostate specific antigen (PSA) blood test (3) the pathologic grade (Gleason score) Princess Margaret Hospital Bristow-Brampton-2009 Bristow-Orillia-2008 University Health Network

Prostate Cancer: Some Basics Prostate Cancer: Some Basics Age and race-adjusted cut-off values for PSA Age Caucasians Blacks Asians 40-49 2.5 2.0 2.0 50-59 3.5 4.0 3.0 60-69 4.5 4.5 4.0 70-80 6.5 5.5 5.0 Source: Prostate Cancer A Guide for Patients, by Dr. Laurence Klotz Bristow-Brampton-2009 Princess Margaret Hospital Bristow-Orillia-2008 University Health Network

Canadian Prostate Cancer Cancer Canadian Prostate Statistics Statistics • In 2007: 22,300 men diagnosed with prostate cancer and 4,300 will die from it • On average, 439 men are diagnosed each week • One in 6 men will be diagnosed with prostate cancer, mostly after the age of 60 • One in 27 will die from it • Test at age 40-50 depending on risk factors Princess Margaret Hospital Bristow-Brampton-2009 Bristow-Orillia-2008 University Health Network

New Cases of Cancer in Men: 2007 New Cases of Cancer in Men: 2007 Princess Margaret Hospital Bristow-Brampton-2009 Bristow-Orillia-2008 University Health Network

Deaths From Cancer in Men: 2007 Deaths From Cancer in Men: 2007 Princess Margaret Hospital Bristow-Brampton-2009 Bristow-Orillia-2008 University Health Network

Treatment Options & Side Effects Treatment Options & Side Effects Indolent Disease Active Disease Aggressive Disease Hormone Therapy Surgery = Radical Prostatectomy (injections/tablets) WATCH WATCH Robots or laprascopic THE PSA THE PSA CAREFULLY CAREFULLY “Active Surveillance” Radiotherapy or brachytherapy (seeds) Chemotherapy Combinations Increasing Stage and Aggression Princess Margaret Hospital Bristow-Brampton-2009 Bristow-Orillia-2008 University Health Network

Risk Groupings and Treatment: Risk Groupings and Treatment: ( Active Surveillance, Surgery, Radiotherapy, Hormone Therapy and ( Active Surveillance, Surgery, Radiotherapy, Hormone Therapy and ) Chemotherapy ) Chemotherapy PROGNOSTIC FACTORS RISK GROUPS • Traditional: T-stage, PSA, • LOW: T1/T2; PSA <10; GS 4-6 Gleason Score ( Brachy, HIFU, Cryo, EBRT; Surgery, AS ) • Newer: Percent Positive Biopsies, Ki-67, PSA DT < 10 months • INTERMEDIATE: T1/T2; GS 7; PSA 10-20 ( Brachy/EBRT +/- Hormones; Surgery, Other ) • Promising: p53, BAX-BCL2, EGFR,MDM2, SURVIVIN, p16 INK4a , Hypoxia, Repair • HIGH: PSA > 20; GS 8-10; T3-T4 ( EBRT + Hormones+/- Chemo; New Agents, Surgery) • Future: New targets and stem cells Princess Margaret Hospital Bristow-Brampton-2009 Bristow-Orillia-2008 University Health Network

The New Era of Prostate Cancer The New Era of Prostate Cancer Research Research • The 20 th century approach to cancer: Seek and destroy •The 21 st century approach: target and control • Personalized genetic medicine • To treat patients with fewer side effects . •To prevent deaths in patients who are currently incurable. Princess Margaret Hospital Bristow-Brampton-2009 Bristow-Orillia-2008 University Health Network

Individual Oncology: Predict- -Change Treatment Change Treatment Individual Oncology: Predict CURATIVE THERAPY CURATIVE THERAPY MINIMAL COMPLICATIONS MINIMAL COMPLICATIONS Androgen- Androgen -Rc Rc Grade 3&4 Grade 3&4 Mutations Mutations Toxicity Toxicity p53/Bcl p53/Bcl- -2 2 Metastases Metastases nd Cancer 2 nd Cancer Hypoxia & 2 Hypoxia & DNA Repair DNA Repair Biomarker Data Biomarker Data Bristow-2004; Adapted after :press2.nci.nih.gov/sciencebehind/snps_cancer

Predict Sensitive and Resistant Predict Sensitive and Resistant Patients Patients Chromosomes Prostate Ca Example: b1 b2 b3 b4 b5 Frozen biopsies from ~250 men Oxygen measurements DNA repair pathways Clinical results RNA ARRAYS TISSUE ARRAYS Bristow-Brampton-2009 Bristow-Orillia-2008

The Last 10 Years The Last 10 Years “Decreased mortality for men with prostate cancer” • New technologies in biology and imaging – Fluorescence In Situ Hybridization (FISH) and DNA/RNA/Protein CHIPs to diagnose mutations (FISH and CHIPs !) – Use of MR techniques to predict tumour spread and response pre- and post- therapy • New biologic targets and new drugs – Challenge is to have individual biomarkers of response • Better use of PSA-DT and kinetic analyses to predict local resistance and systemic spread – Choose those patients who require local and systemic therapy – Select best patients for best salvage therapies • 10 years of improved technology : – Hypofractionation, precision targeting, IMRT, robotics, HIFU, cryotherapy, sub- prostate targeting, less side-effects Princess Margaret Hospital Bristow-Brampton-2009 Bristow-Orillia-2008 University Health Network

Precision- -Guided Radiotherapy to Kill Cancer Guided Radiotherapy to Kill Cancer Precision Cells and Protect Normal Cells Cells and Protect Normal Cells High Dose Low Dose To Cancer To Normal Cells Princess Margaret Hospital University Health Network

Princess Margaret Hospital University Health Network Daily CT Image Guidance Cone-beam CT (CBCT) + soft C. Catton tissue

A randomized trial of a shorter fractionation schedule for localized intermediate risk prostate cancer. Sponsor: Ontario Clinical Oncology Group (OCOG) Intermediate risk localized prostate cancer Randomize 602 patients 602 patients CTV: Prostate + base of SV CTV: Prostate + base of SV 78Gy/39fractions/8wks 60Gy/20fractions/ 4wks (on-line organ localization) (on-line organ localization) Follow Q6 monthly PSA, DRE, Toxicity Primary endpoint: Secondary endpoints: 1. Biochemical-Clinical Failure (BCF) 5-year bRFR 2. Prostate Cancer Specific Survival Non-inferiority design 3. Toxicity 4. Quality of Life (EPIC and SCF-12)

Patient- -Unique Tissue Unique Tissue Patient Anatomy And Physiology Anatomy And Physiology Roach, JCO, 2007 Princess Margaret Hospital Bristow-Brampton-2009 Bristow-Orillia-2008 University Health Network

PMH Precision-Guided Therapy New PHYSICAL techniques are being developed in an attempt to • lessen the damage to surrounding tissue such as 3-dimensional conformal radiation therapy (3-D CRT) – Great ! Now add Biological Precision !! Princess Margaret Hospital Bristow-Brampton-2009 Bristow-Orillia-2008 University Health Network

The Cell’s Chromosomes and DNA The Cell’s Chromosomes and DNA Hold Important Information Hold Important Information

DNA Breaks: A Way To Kill DNA Breaks: A Way To Kill Cancer Cells With Therapy Cancer Cells With Therapy Pisansky, 2006 Princess Margaret Hospital University Health Network Bristow-Brampton-2009 Bristow-Orillia-2008

Measuring Radiotherapy- -Induced DNA Breaks Induced DNA Breaks Measuring Radiotherapy DNA Breaks Princess Margaret Hospital University Health Network

Aggressive Cells Develop in Poorly- -Oxygenated (Hypoxic) Oxygenated (Hypoxic) Aggressive Cells Develop in Poorly Prostate Cancer Cells: Why ? Prostate Cancer Cells: Why ? Cancer Hypoxia is linked to increased Cancer Hypoxia is linked to increased Normal metastatic spread, chromosomal spread, chromosomal metastatic instability and resistance to instability and resistance to chemo- - and radiotherapy. and radiotherapy. chemo How/Why? How/Why? Cancer Princess Margaret Hospital Bristow-Brampton-2009 Bristow-Orillia-2008 University Health Network

DNA Breaks & O 2 : A Way To Kill DNA Breaks & O 2 : A Way To Kill Cancer Cells With Therapy Cancer Cells With Therapy DNA-dsb Oxygen Enhancement Ratio (OER) = Hypoxic cells 2-3x more resistant Princess Margaret Hospital University Health Network Bristow-Brampton-2009

Chemotherapy: Decreased Penetration Chemotherapy: Decreased Penetration and Non- -cycling Cells cycling Cells and Non Doxorubicin Minchinton and Tannock, Nat Rev Can, 2006 Princess Margaret Hospital University Health Network Bristow-Brampton-2009

Measuring Oxygenation: Measuring Oxygenation: Eppendorf pO2 Probe pO2 Probe Eppendorf Prostate: trans- -rectal rectal Eppendorf Eppendorf Prostate: trans Electrode & biopsies Electrode & biopsies Princess Margaret Hospital Bristow-Brampton-2009 Bristow-Orillia-2008 University Health Network

Prostate Patient pO 2 Data Prostate Patient pO 2 Data Milosevic, Parker, Chung, Bristow et al. Can Res; 2008 Princess Margaret Hospital University Health Network Bristow-Brampton-2009