Multiple Myeloma
Definition: Multiple myeloma (also known as myeloma or plasma cell myeloma) is a progressive hematologic (blood) disease. It is a cancer of the plasma cell
Multiple Myeloma
Presented by:G. MICHAEL WHITEHEAD
Multiple Myeloma
Multiple Myeloma
Presented by:Mike Lynch
Hypercalcemia and Multiple Myeloma
Multiple Myeloma
Presented by:Rozina Mithani
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Glioblastoma Multiforme Treatment Options
Glioblastoma multiforme (GBM) is the most common and most aggressive type of primary brain tumor
Patient History
Primary Intracranial CNS Tumors
Gliomas
* Astrocytomas
o Pilocytic Astrocytomas (grade 1)
o Diffuse Astrocytomas (grade 2)
o Anaplastic Astrocytomas (grade 3)
o Glioblastoma Multiforme (grade 4 – 50%)
* Oligodendrogliomas
o Low Grade Oligodendroglioma (grade 2)
o Anaplastic Oligodendroglioma (grade 3)
* Mixed Oligoastrocytomas
o Low Grade Oligoastrocytoma (grade 2)
o Anaplastic Oligodendroglioma (grade 3)
Clinical Presentation
* Symptoms caused by mass effect or destruction of normal tissue
* Symptoms
o Headache
o Seizures
o Neurological Deficits
+ Personality Changes
+ Slowing of Motor Function/Hemiplegia
+ Hallucinations
+ Memory Impairment
+ Vision Impairment
Prognosis for GBM
* Mean survival 12-14 months from diagnosis
* Mean survival 4-5 months from recurrence
* 2 year survival 10%
* Recurrence occurs within 2-3 cm of the margins of the original tumor in 80% of patients
Prognostic Factors in GBM
* Age
* Performance status
* Neurologic functional status
Treatment
* Surgery
* Radiation
* Chemotherapy
Treatment - Surgery
* Surgery done for diagnosis and to relieve symptoms when possible
* Median survival after surgery alone is 3-4 months
* Resections are suboptimal secondary to preservation of normal brain tissue
* Re-excision at recurrence an option in patients with good performance status
Treatment - Radiation
* Radiation after surgery extends median survival to 9-11 months
* CNS tumors infiltrate into surrounding normal brain tissue up to 3 cm or more
* Radiation delivered on a focal field including the tumor bed with a 2-3 cm margin with total dose of 58-60 Gy
Treatment - Chemotherapy
* Nitrosoureas (BCNU/CCNU)
o Best known chemotherapy agents
o Metaanalysis showed increase in median survival of 2 months over surgery and radiation alone
o BCNU impregnated wafers show similar results to systemic therapy
* PVC (Procarbazine, CCNU, Vincristine)
* Temozolomide
* Thalidomide
* Tamoxifen
* BCNU + O6-Benzylguanine
* Gleevec
Conclusions
* Glioblastoma multiforme continues to have a dismal prognosis
* Significant work has been done to identify genetic pathways in glioma progression
* Genetic information being used to identify targets for therapies and has potential to identify chemotherapy responsive tumors
Glioblastoma Multiforme Treatment Options.ppt
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The Ins and Outs of ColoRectal Cancer
Pesentation By: Kelly Hann
Anatomy
American Cancer Society
Signs & Symptoms
Aids in diagnosing & preventing colon cancer
Physical Exam
Fecal occult blood test
Digital Rectal Exam
Barium Enema
What does a Barium Enema do?
How can one prepare for this test?
Types of Barium Enemas
Air Contrast (Double contrast)
Post Barium Enema instructions
Results
Pros of Barium Enema
Cons of Barium Enema
Sigmoidoscopy
Procedure Detection
Preparation Complications
Colonoscopy
Virtual or (CT) Colonography
Prognosis (chances of recovery)
Treatment Options
Surgery
Surgery for Rectal Cancer
* Pelvic Exenteration:
Radiation Therapy
Chemotherapy
Risk Factors
Dietary Risk Factors
Survival Rates
Closing Points
The Ins and Outs of ColoRectal Cancer.ppt
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Liver and Biliary Tract-Tumors
Presentation lecture by:Inga Gurevich, MD, PhD
Liver - Benign Tumors and Tumor Like Conditions
* Focal nodular hyperplasia
* Liver cell adenoma
* Hemangioma (most common benign lesion)
* Mesenchymal hamartoma
Focal nodular hyperplasia (FNH)
* Common (#2 liver tumor after hemangioma)
* Mass lesion of young (median age 38 years); some studies show female predominance
* Represents 2-10% of pediatric hepatic tumors
* May be associated with oral contraceptives (66-95% of cases), hepatic cavernous hemangioma (20%), glycogen storage disease type Ia, portal hypertension
* Tumors associated with oral contraceptives often have hemorrhage, necrosis, infarction
* Usually an incidental finding; present in 1% of autopsies
* Xray: mass with central scar, centrifugal hypervascularity by angiography; CT and MRI are important,
* Treatment: excellent prognosis; discontinue oral contraceptives, if applicable; surgery if symptomatic, complications, compression of adjacent organs or lesion progression
* Well-demarcated, subcapsular, light brown to yellow ; bulging nodule, 70-80% solitary, up to 5 -10cm; has central gray-white stellate scar (unless < 1 cm) from which fibrous septa radiate to periphery and create multiple smaller nodules; hemorrhage, necrosis, infarction, bile staining often seen; larger tumors may have multiple scars; adjacent liver is normal
* Micro: Most tumors (80%) have the 3 classic features of abnormal architecture, bile ductular proliferation and malformed vessels.
* Non-classic forms lack either abnormal architecture or malformed vessels, and are divided into three types - (a) telangiectatic, (b) mixed hyperplastic and adenomatous or (c) atypia of large cell
* Positive stains: alpha-1-antitrypsin
* Negative stains: p53, CD143 (angiotensin I-converting enzyme: reduced expression
* DD: Osler-Weber-Rendu disease, Budd-Chiari syndrome or cirrhosis (adjacent liver is not normal), fibrolamellar hepatocellular carcinoma (marked atypia of hepatocytes), hepatocellular adenoma (encapsulated, monoclonal)
Liver Cell Adenoma
Hemangioma
Mesenchymal Hamartoma
Liver Cell Tumors - Malignant
* Hepatocellular carcinoma
* Hepatoblastoma
* Epithelioid hemangioendothelioma
* Angiosarcoma
* Undifferentiated (embryonal) sarcoma
* Squamous Cell Carcinoma
* Carcinoid Tumor
* Lymphoma/leukemia
Hepatocellular carcinoma
Clear cell variant of hepatocellular carcinoma
Fibrolamellar Variant of Hepatocellular Carcinoma
Hepatoblastoma
Epithelioid Hemangioendothelioma
Angiosarcoma
Undifferentiated Sarcoma
Bile Duct Tumors
Bile Duct Adenoma
Biliary Cystadenoma
Biliary Cystadenocarcinoma
Cholangiocarcinoma (intrahepatic)
case studies ..
Liver and Biliary Tract-Tumors.ppt
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Treatment for Chronic Hepatitis B
Screening for Hepatocellular Carcinoma
Presentation by:Mindie H. Nguyen, MD, MAS
Assistant Professor of Medicine
Division of Gastroenterology & Hepatology
Stanford University Medical Center
Chronic Hepatitis B
HBV Disease Burden in Asian-Americans
Hepatitis B Prevalence
Etiology of HCC in Asians
Impact of HBV DNA and ALT Levels on Disease Outcomes
Disease Progression and HCC Risk
Impact of Viral Load
* High viral load:
* Reduction in viral load:
HBV DNA Associated with Increased Risk of HCC
HBV DNA levels and Risk of Cirrhosis and HCC REVEAL-HBV Study
HBV DNA Levels Predict Risk of Developing Cirrhosis
Viral Load Is the Main Predictor of Cirrhosis Regardless of Serum ALT
HBV DNA Levels Predict Risk of Developing HCC
Dose-Response Relationship:
HBV DNA and HCC
HBV DNA Levels are Associated With Clinical Outcomes (HCC)
REVEAL-HBV Study: Cirrhosis Analysis Conclusions
REVEAL-HBV Study: HCC Analysis Conclusions
Impact of Treatment on Disease Progression
Primary Goal of Treatment
Rapid and sustained suppression of HBV to the lowest possible level1,2 Outcomes
Rapid and Profound HBV Suppression: an Important Therapeutic Goal
Lamivudine and Disease Progression and HCC incidence in Advanced HBV (stage III/IV)
HBV DNA Suppression Reduces Cirrhosis Progression
Lamivudine
Placebo
Diagnosis of HCC
HBV DNA Suppression Reduces HCC Incidence Rate
Conclusions
Summary
* HBV DNA is an essential marker for predicting risk for complications
* Viral suppression is associated with improved treatment outcomes in patients with advanced fibrosis.
* Emerging potent antiviral therapies provide the potential for more effective treatment response and prevention of complications of CHB
Screening for Hepatocellular Carcinoma
Screening for HCC Consensus Recommendations
HCC: Screening Tests
Changes in sensitivity and specificity of AFP for diagnosis of HCC using various cut-offs
WHO Principles of Screening
Screening improves survival
HCC Screening: clinical studies
Pseudo-Disease
RCT for HCC Screening
Cost-Effectiveness of Screening: Other Cancers
Cost-Effectiveness of HCC Screening
Real-life studies with cost information:
Screening for HCC: Summary
Treatment for Chronic Hepatitis B.ppt
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Hepatocellular Carcinoma: Screening, Diagnosis, and Treatment
Presentation lecture by: Catherine Frenette, MD
California Pacific Medical Center
The Barry S. Levin Department of Transplantation
Hepatocellular Carcinoma
Increasing prevalence of patients with cirrhosis
Regional Variations in HCC-related Mortality
Risk Factors for HCC
Chronic Hepatitis
Cirrhosis
HCC
Chronic HBV Infection
Inactive Carrier State
Chronic Hepatitis
Clinical Outcome of Chronic Hepatitis B
HCC Epidemiology
HBV DNA Associated with Increased Risk of HCC
Primary Prevention of HCC
Surveillance Recommendations
Surveillance for HCC Prolongs Survival
Cost-Effectiveness of HCC Surveillance
Quad Phase Imaging of Hepatocellular Carcinoma
Liver transplantation
Curative treatments
Randomized controlled trials
HCC: Barcelona Clinic Liver Cancer
Staging Classification
Factors Determining Prognosis of Hepatocellular Cancer
Management of Hepatocellular Carcinoma
Newer modalities
Surgical Resection: Indications
Liver Transplantation
UNOS Criteria for Liver Transplantation for HCC
Liver Transplantation for HCC
Months After Transplantation Patients at Risk
Liver Transplantation for HCC: Outcomes Applying Milan Criteria
Liver Transplantation for HCC UCSF Criteria
Differentiated histology
Local Ablation Therapy for Transplant Candidates
Trans-Arterial Chemoembolization TACE
Catheter-Based Therapies
TACE for HCC
Radiofrequency Ablation
RFA Modalities
RFA Indications
RFA Contraindications
RFA Complications
Radiographic Outcomes
New Therapies Under Investigation
Chemotherapy
* Sorafenib* (Nexavar)
* Erlotinib (Tarceva)
* Sirolimus (Rapamune)
* Capecitabine (Xeloda)
* Floxuridine (FUDR)
* Bevacizumab (Avastin)
* Sargramostim (Leukine)
* Oxaliplatin (Eloxatin)
* Imatinib (Gleevac)
Local Therapy
Yttrium-90 Microspheres
Doxorubicin Eluting Beads
Systemic chemotherapy
GI Intergroup Recommendations
Macrovascular invasion or Metastases
Supportive Care
Conclusion
* Screening saves lives
* Resection or Transplantation best option
* RFA used for unifocal lesions < 5 cm
* TACE used for multifocal, lesions > 5 cm
o Non surgical candidates
* Combination therapies
o TACE and RFA
* New Strategies
o Yttrium-90 theraspheres
o Drug Eluting microspheres
* Sorafenib used when local treatment not an option
Hepatocellular Carcinoma: Screening, Diagnosis, and Treatment.ppt
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Angiogenesis-Dependent Disease
Dr. Judah Folkman is the originator of the field of angiogenesis research and the idea that blood vessel growth is a key target in cancer treatment. One drug developed from this field of study is the newly approved drug Avastin. In this lecture, Dr. Folkman discusses his research on angiogenesis and his thoughts on future cancer treatments. This lecture is part of the Frontiers in Cancer Research series of public talks at UC Santa Barbara. App. 90 minutes video
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Food Fitness and Prostate Cancer
Alan R. Kristal, Dr.P.H., M.P.H., professor of epidemiology at the University of Washington and associate head of the Cancer Prevention Research Program at the Fred Hutchinson Cancer Research Center, present on food, fitness and Prostate Cancer for mens health. App. one hour video
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Reducing the Chances of Getting Cancer: What are the Options
Dr. Robert Hiatt is the Director of Population Science and Deputy Director of the UCSF Comprehensive Cancer Center. As an epidemiologist he explores effective and efficient approaches to cancer prevention and treatment. App. 90 minutes video
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Possible 75% cancer mortality reduction with Vitamin D
In a new study, researchers at the Moores Cancer Center and Department of Family and Preventive Medicine, UC San Diego used a complex computer prediction model to determine that intake of vitamin D3 and calcium would prevent 58,000 new cases of breast cancer and 49,000 new cases of colorectal cancer annually in the US and Canada. The researchers model also predicted that 75% of deaths from these cancers could be prevented with adequate intake of vitamin D3 and calcium. Dr. Cedric Garland, UCSD School of Medicine, lead researcher on the study discusses the implications of this finding and the proposed actions. 5 minutes video
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Removal of Brest medically termed as Mastectomy. The operation takes from two to three hours, with three to five weeks for full recovery. Watch this 5 minutes video
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Hair Growth Show Starting 6 Weeks After Chemotherapy
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Chemotherapy Process - Video
Chemotherapy-chemotherapy process A consultant medical oncologist explains the chemotherapy process and patients talk about their own experiences of the treatment.
3.45 minutes video
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Actinic keratosis - Stage One of Skin Cancer
Actinic keratosis,is a premalignant condition of thick, scaly, or crusty patches of skin. It is more common in fair-skinned people, especially those who are frequently exposed to the sun, as it is usually accompanied by solar damage. Since some of these pre-cancers progress to squamous cell carcinoma, they should be treated. When skin is exposed to the sun constantly, thick, scaly, or crusty bumps appear. The scaly or crusty part of the bump is dry and rough. The growths start out as flat scaly areas, and later grow into a tough, wart-like area. An actinic keratosis site commonly ranges between 2 and 6 millimeters in size, and can be dark or light, tan, pink, red, a combination of all these, or have the same pigment as the surrounding skin. It may appear on any sun-exposed area, such as the face, ears, neck, scalp, chest, backs of hands, forearms, or lips.
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Cancer Education Slides
from cancer.net
Chronic Lymphocytic Leukemia
What is Cancer?
What is Chronic Lymphocytic Leukemia (CLL)
What is the Function of Lymphocytes
What are the Types of CLL
What are the Risk Factors for CLL
What are the Symptoms of CLL
How is CLL Diagnosed
CLL Staging
Stage 0 CLL
Stage I CLL
Stage II CLL
Stage III CLL
Stage IV CLL
Risk Groups of CLL
European Staging System (Binet Classification)
How is CLL Treated?
* Treatment depends on the patient’s stage, risk status and overall health
* Watch and wait option: many people may not require treatment right away
* Chemotherapy
* Biologic therapy
* Radiation therapy
* More than one treatment may be used
* Use of drugs to kill cancer cells
CLL Treatment: Biologic Therapy
CLL Treatment: Radiation Therapy
Supportive Treatment for CLL
Current Research: Stem Cell Transplantation
Current Research: Other Areas
The Role of Clinical Trials for the Treatment of CLL
Clinical Trials: Patient Safety
Clinical Trials: Phases
Clinical Trials Resources
Coping with Side Effects
More Information
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Emerging Applications In Clinical Radiation Oncology
by
Ross A. Abrams, M.D.
Topics
* Integration of Emerging Results From Molecular Biology Into Patient Selection and Treatment Strategies
* Integration of Enhanced Technology Into Clinical Practice
* Moving Beyond Photons (X-Rays) to Charged Particles (Protons, Heavy Ions)
Integration of Emerging Results From Molecular Biology
* Combining Radiotherapy With Targeted Therapy
* Using Genomics, Proteomics, Metabolomics to Help Define Prognosis
* Using Genomics, Proteomics, Metabolomics to Help Define Treatment
Cetuximab
Clinical Activity
* Colorectal Cancer
* Head and Neck
Side Effects – Minimal
* Infusion Reactions
* Rash
* Asthenia
* N/V/D
Radiation Synergies
* EGFR Blockade Results in Radiation Sensitization
* EGFR Expression Upregulated by Irradiation
Combining Radiotherapy With
Cetuximab + Radiotherapy
Minimal Increase in Toxicity
Other Target Agents Showing Promise w/ XRT
Integration of Emerging Results From Molecular Biology
* Combining Radiotherapy With Targeted Therapy
* Using Genomics, Proteomics, Metabolomics to Help Define Prognosis
* Using Genomics, Proteomics, Metabolomics to Help Define Treatment
Chung/Torres-Roca, et al.: Genomics for prognosis and treatment response prediction
Formalin Fixed Tissue Data Set:
Integration of Enhanced Technology
* Metabolic Imaging To Define/Refine Targeting – Prostate/Lung Cancer
* Body Stereotactic Therapy – Lung Cancer
* Image Guided Radiotherapy (IGRT)
* Physiologic Gating – Lung/GI Cancers
* Integrating Metabolic Imaging, IGRT, Gating with IMRT
Metabolic Imaging to Refine Rx & XRT Targeting
MRI Imaging To Refine XRT Boost:
Prostate cancer
Enhancing IMRT With Image Guidance
IMRT 3D
Image-Guidance
* Rigid Immobilization
o Stereotactic systems
* Ultrasound Guidance
o Pelvic ultrasound
* CT Guidance
o CT scanner in the treatment room
o Helical tomotherapy
3 cGy Verification CT
Soft Tissue Window
Tools for Patient Registration
Moving Beyond Photons
* Protons
* Intensity Modulated Proton Therapy
* Heavy Particle Therapy (Carbon)
Carbon Ion Radiotherapy:
Protons on Steroids!
LET and RBE of Carbon Ion Therapy
Dose vs. Biologic Effect:LET
Conclusions
Radiotherapy is evolving technologically through enhanced dose delivery and precision and biologically through enhanced understanding of factors that define or reveal tumor location, behavior, and/or vulnerabilities
Emerging Applications In Clinical Radiation Oncology
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Oncology biomarkers for safety and efficacy
by
David Ross, M.D., Ph.D.
Office of Oncology Drug Products
Center for Drug Evaluation and Research
U.S. Food and Drug Administration
* Why biomarkers?
* Biomarkers for safety
* Biomarkers for efficacy
* Scientific and regulatory challenges
* FDA views pharmacogenomics and biomarkers as part of a new paradigm for oncology therapeutics development
* Developing new cancer treatments via biomarkers will require a coordinated public-private approach between academia, industry, government, and other stakeholders
Development issues in oncology – I
* Represents >100 diseases/indications
o Different natural histories
o Different etiologies/molecular biology
* Efficacy assessment is difficult
o Most investigational therapies fail to show efficacy
o Even promising agents may have small treatment effects
* Safety assessment is difficult
o most candidates (even targeted) are toxic
o underlying disease may confound safety assessment
* Investigational nature of discipline
o cancer centers, cooperative groups, NCI
* Multi-disciplinary approaches
o chemotherapy, biologics, surgery, radiation therapy, devices, supportive care, diagnostics
Development issues in oncology – II
* Life-threatening nature of diseases
* Potential for distant recurrences
* Drugs have multiple MOAs; used in combination
* Risk/benefit ratio--different perspective on serious adverse events; highly trained specialists using drugs rather than GP
* Off-label uses may be standard of care
* New technologies/concepts piloted in oncology
Research vs. results
The paradox of drug development
1. Clinical trials provide evidence of efficacy and safety at usual doses in populations
2. Physicians treat individual patients who can vary widely in their response to drug therapy
All patients with same diagnosis
Therapy C
Therapy B
Therapy A
Some respond to treatment
Some don’t
Some develop adverse reactions
Why the differences in response?
Standard therapy
Responders and Patients
Not Predisposed to Toxicity
All patients with same diagnosis
Alternate therapy
non-responders
and toxic responders
Responding to variability
Pharmacogenomics applied to oncology therapeutics development
GCCCACCTC
GCCCGCCTC
Evolution of pharmacogenomics
* Phenotypic variation known for >50 y
o Isoniazid rapid acetylators, G6PD-associated hemolysis
o Application required development of new assay for each phenotype
* Sequencing of entire human genome
* Genotype – drug response correlations
* Analytic biochemistry advances
o Development of bioinformatics
o Multiplex gene analysis platforms
o Application of fluidics and IC manufacturing techniques to gene chip fabrication
* Oncology therapeutic strategies
o Clinically relevant genotypes identified
o Development of validated assay for genotype
o Safety – correlation of clinical risk with genotype
o Efficacy – clinical benefit via genotype targeting
Irinotecan (Camptosar®)
* Irinotecan ~ proven 1st (5-FU and leucovorin) and 2nd line prodrug therapy for metastatic colon/rectal cancer
* Providers/patients face a clinical predicament ~ what is the optimal dose?
o Incidence of grade 3-4 neutropenia is 35%
o Nearly 70% of patients need dose reduction
o Toxicity associated with active drug exposure
Irinotecan metabolism
UGT1A1 gene structure
UGT1A1: promoter polymorphism and toxicity
* Prodrug (irinotecan) metabolized to SN-38 (active drug)
* Rate-limiting metabolic enzyme encoded by UGT1A1
* Five exons
* Promoter contains run of TA repeats; most common allele has 6 repeats; unusual allele has 7
Problem: accumulation of SN-38
* Exposure dependent on metabolism of camptosar by UGT1A1
o Wide interpatient variability in UGT1A1 activity
o Patients with *28 variant (7 TA repeats) have reduced enzyme activity
o Homozygous deficient (7/7 genotype) patients have the greatest risk of neutropenia
o Neutropenia matters to patients
* Original label was silent on UGT information; approved dose not optimized
UGT1A1 TA repeat→irinotecan neutropenia
Camptosar Label Revised and FDA Approved UGT Test
“Individuals who are homozygous for the UGT1A1*28 allele are at increased risk for neutropenia following initiation of CAMPTOSAR treatment. A reduced initial dose should be considered for patients known to be homozygous for the UGT1A1*28 allele (see DOSAGE AND ADMINISTRATION). Heterozygous patients (carriers of one variant allele and one wild-type allele which results in intermediate UGT1A1 activity) may be at increased risk for neutropenia; however, clinical results have been variable and such patients have been shown to tolerate normal starting doses.”
EGFR as a therapeutic target
o Epidermal growth factor receptor (EGFR) gene (erbB1) first sequenced in a four-member family of structurally related type or subclass 1 receptors known as tyrosine kinases.
o Critical for mediating the proliferation and differentiation of normal cell growth
o Widely expressed in epithelial, mesenchymal, and neuronal tissues
o Aberrant activation of the kinase activity of these receptors appears to play a primary role in solid tumor development and/or progression
o Breast, brain, lung, cervical, bladder, gastrointestinal, renal, and head and neck squamous cell carcinomas, have demonstrated an over expression of EGFR relative to normal tissue, which is associated with a poor clinical prognosis
Erlotinib (Tarceva®)
* Potent EGFR tyrosine kinase inhibitor
o MW 428 Da
o IC50 20 nM
* Pre-clinical anti-tumor activity
o Inhibits tumor cell line growth
o Activity in mouse xenograft models
* Increased RR, PFS, and OS in Phase 3
Current pharmacogenomic examples
* bcr/abl or 9:22 translocation—imatinib mesylate (Gleevec)*
* HER2-neu—trastuzumab (Herceptin)**
* C-kit mutations—imatinib mesylate (Gleevec)**
* Thiopurine S-methyltransferase—mercaptopurine and azathioprine*
* UGT1A1-irinotecan (Camptosar)**
* Cytochrome P-450 (CYP) 2D6—5-HT3 receptor antagonists and codeine derivatives*
* *-FDA package insert information
* *-FDA-approved device
Scientific challenges
* Biomarker/transcript profile selection
* Definition of response predictors
* Assay development
o Platform and reagent standardization
o Defining sensitivity
o Minimizing variability
* Pharmacodynamic modeling
* Biomarker validation
* Biomarker ≠ surrogate
Regulatory challenges
* Ensuring assay reliability/validity
* Addressing drug/diagnostic co-development
* Understanding physiologic, toxicologic, and clinical significance of biomarkers
* Defining criteria for biomarker validation
* Extrapolation across populations
* Endpoint definitions
* Addressing exclusion of patients without target
* Defining standards for transmission, processing, and storage of pharmacogenomic data
* Communication with diverse stakeholders
Platform standardization
Summary
* Biomarkers hold enormous promise
o Conventional oncology development - small benefit in a large patient population
o Targeted drug development – may define large benefit in smaller population
* The devil will be in the details
* New development structures must be built
o Flexible regulatory mechanisms
o Need for drug-device co-development paradigm
o Need for new partnerships between industry, government, academics
FDA Pharmacogenomic Guidances
March 2004, CDER:
Pharmacogenomic Data Submissions
http://www.fda.gov/cber/gdlns/pharmdtasub.htm
April 2005, CDER/CDRH/CBER/OCP:
Drug-Diagnostic Co-development Concept Paper http://www.fda.gov/cder/genomics/pharmacoconceptfn.pdf
February 2006, CDRH:
Multiplex Tests for Heritable DNA Markers, Mutations and Expression Patterns: Draft Guidance for Industry and FDA Reviewers http://www.fda.gov/cdrh/oivd/guidance/1549.pdf
Oncology biomarkers for safety and efficacy
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Working with FDA: Biological Products and Clinical Development
by
Eda T. Bloom, Ph.D.
Chief, Gene Transfer and Immunogenicity Branch
Office of Cellular, Tissue, and Gene Therapies
Division of Cellular and Gene Therapies
Center for Biologics Evaluation and Research
FDA
Outline
* FDA organization
* Products regulated
* Critical path issues in the development of cell based products
OCTGT Regulated Products
* Products with Cancer indications
o Cellular therapies
o Tumor vaccines
o Gene therapies
o Tissue and tissue based products
o Combination products
o Anti-idiotype antibodies
* Products generally not used for cancer
o Xenotransplantation products
o Devices used for cells/tissues
Therapeutic Biological Products Regulated by CDER
* Monoclonal antibodies for in vivo use.
* Proteins intended for therapeutic use
o Includes cytokines (e.g. interferons), growth factors, enzymes (e.g. thrombolytics), and other novel proteins, except for those that are specifically assigned to CBER (e.g., vaccines and blood products).
o Includes therapeutic proteins derived from plants, animals, or microorganisms, and recombinant versions of these products.
* Immunomodulators (non-vaccine and non-allergenic products intended to treat disease by inhibiting or modifying a pre-existing immune response).
FDA Perspectives (CMC)
* Greater product knowledge (mechanism of action, characterization, etc) will aid in developing meaningful assays and/or novel approaches for product characterization and comparability
o Potency and identity testing should provide meaningful information about the product prior to its release
* Control of manufacturing process is key to producing consistent biological products
* A flexible approach and open communication is needed by both regulators and product developers
Potential CMC Issues for
Biological Products
* Some unique concerns for cell/gene therapy products
o Replication competent viruses
o Oncolytic viruses
o Cell/tissue source
* Some unique concerns for protein products
o Post-translational issues
+ Isoforms
+ Glycosylation
o Aggregates
* Examples of cross-cutting concerns
o Immunogenicity
o Animal components
o Formulation, delivery, stability
o Identity, purity, potency, comparability
Key Points to Consider for Pharmacology/Toxicology Testing
* Preclinical testing paradigm is influenced by:
o Data from previous preclinical studies on all components and combination
o Data from previous clinical studies (pre- and post-marketing) on all components and combination
o Regulatory status of each component
* Provide safety and activity data for individual components and combination in appropriate animal models by intended clinical route of administration
Potential PT Issues for Biological Products
* Some unique concerns for cell/gene therapy products
o Insertional mutagenesis
o Alteration of germline
o Long-term toxicity
o Migratory potential
* Some unique concerns for protein products
o Immune-mediated problems
+ Immune complexes
+ Obfuscation of toxicity
+ Allergy
o Species specificity
* Examples of cross-cutting concerns
o Picking the relevant animal model
o Dosing, safety
o Biodistribution
o Toxicity, tumorigenicity
o Immunogenicity (rejection/elimination)
Science in Research and Review:
Critical Path Initiative
* Bring scientific advances to medical product development process (simulation models, validated biomarkers, new clinical trial designs)
* Stimulate development of applicable research programs in critical path scientific areas, aim to develop techniques that address challenges encountered during product development
* Regulatory guidance/practice and standards to reflect best available science, integrate FDA involvement
OCTGT Research Program Areas
* Virology
o Retroviruses, adeno, herpes, PERV
* Immunology
o Host-vector interactions, transplant rejection
* Cell biology
o Control of differentiation in animal models, stem cell biology
* Cancer biology
o Molecular biomarkers, animal models
* Biotechnology
o Microarray, flow cytometry
Cell Therapy Product Characterization
* Morphologic evaluation
* Unique biochemical markers
* Gene and protein expression analysis
* Cellular impurities profile
* Biologic activity/Potency
* Identity: HLA, other unique marker
Developmental Stages
Characterization
Gene expression profile, Antibodies, Enzymes,
In vitro differentiation
Manufacturing Concerns
Exogenous Influences
Cell-cell interaction
Growth factors
Lot Release
Identity
Potency
Safety
Viability
Manufacturing
Cell Banks
Cell Characterization
Testing and Screening
Donors, Viruses, Genetic defects?
Tumorigenesis
mutation
Apoptosis
Self renewal
Commitment
Differentiation
are covered in this presentation.
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Two Models of Medical Error Reduction Programs in Radiation Oncology
by
Ed Kline
RadPhysics Services LLC
Albuquerque, NM, © RPS
Introduction
* This presentation describes the design, implementation, and results of two QA/medical error reduction programs
* Both programs are designed for
o Reducing preventable systems-related medical errors (i.e., sentinel events, “near misses”)
o Preventing violations of regulatory requirements (i.e., State/NRC)
o Ensuring compliance with recommended standards (i.e., JCAHO, ACR, ACRO, etc.)
History
* Institute of Medicine (IOM) report5
o Focused a great deal of attention on the issue of medical errors and patient safety
o 44,000 to 98,000 deaths per year in U.S. hospitals each year as the result of medical errors
o 10,000 deaths per year in Canadian hospitals
o Exceeds annual death rates from road accidents, breast cancer, and AIDS combined in U.S.
To Err is Human: Building a Safer Health System.
* Key legislation
o Patient Safety Quality Improvement Act9
+ Certifies patient safety organizations in each State to collect data and report on medical errors
o State Patient Safety Centers
+ In past 5 years, 6 states have enacted legislation supporting creation of state patient safety centers
+ 5 of the 6 states now operate patient safety centers
+ Separate mandatory reporting systems for serious adverse events
+ Centers are housed within state regulatory agencies
Reducing Medical Errors, Issue Module, Kaiser EDU.org, Accessed through www.kaiseredu.org.
* Patient safety centers include10
o The Florida Patient Safety Corporation
o The Maryland Patient Safety Center
o The Betsy Lehman Center for Patient Safety and Medical Error Reduction (Massachusetts)
o The New York Center for Patient Safety
o The Oregon Patient Safety Commission
o The Pennsylvania Patient Safety Authority
State Patient Safety Centers: A New Approach to Promote Patient Safety, The Flood Tide Forum, National Academy for State Health Policy, 10/04, Accessed through www.nashp.org.
* State reporting: mandatory vs voluntary11
o Mandatory reporting: Colorado, Florida, Kansas, Nebraska, New York, Ohio, Pennsylvania, Rhode Island, South Carolina, South Dakota, Tennessee, Texas, Washington
o Voluntary reporting: District of Columbia, Georgia, New Mexico, North Carolina, Oregon, Wyoming
o Considering new legislation: Arizona, California, Maine
o Mandatory reporting but considering new legislation: Massachusetts, New Jersey
National Conference of State Legislatures, National Academy for State Health Policy, 12/03, Accessed through www.nashp.org.
* JCAHO revises standards
o Patient safety standards effective 7/1/01
o Requires all JCAHO hospitals (5,000) to implement ongoing medical error reduction programs
o Almost 50 percent of JCAHO standards are directly related to safety
Patient Safety - Essentials for Health Care, 2nd edition, Joint Commission on Accreditation of
Healthcare Organizations. Oakbrooke Terrace, IL: Department of Publications, 2004.
* JCAHO’s sentinel event policy13
o Implemented in 1996
o Identify sentinel events
o Take action to prevent their recurrence
o Complete a thorough and credible root cause analysis
o Implement improvements to reduce risk
o Monitor the effectiveness of those improvements
o Root cause analysis must focus on process and system factors
o Improvements must include documentation of a risk-reduction strategy and internal corrective action plan
o Action plan must include measurements of the effectiveness of process and system improvements to reduce risk
Sentinel Event Policies and Procedures - Revised: July 2002, Joint Commission on Accreditation of Healthcare Organizations, Accessed through www.jcaho.org/accredited+organizations/long+term+care/sentinel+events/index.htm.
* JCAHO’s Office of Quality Monitoring
o Receives, evaluates and tracks complaints and reports of concerns about health care organizations relating to quality of care issues
o Conducts unannounced on-site evaluations
* JCAHO and CMS agreement14
o Effective 9/16/04
o Working together to align Hospital Quality Measures (JC’s ORYX Core Measures and CMS’7th Scope of Work Quality of Core Measures)
Joint Commission, CMS to Make Common Performance Measures, Joint Commission on Accreditation of Healthcare Organizations, Accessed through www.jcaho.org/accredited+organizations/long+term+care/sentinel+events.
* CMS quality incentives15
o Quality Improvement Organizations (QIOs)
+ Contracted by CMS to operate in every State
+ 67% of QIOs perform independent quality audits
o Premier Hospital Quality Initiative
+ 3-year demonstration project recognizes and provides financial reward
+ CMS partnership with Premier Inc., nationwide purchasing alliance
+ Hospitals in top 20% of quality for specific diagnosis get financial reward
# Top decile gets 2% Diagnosis Related Group (DRG) bonus
# 2nd decile get 1% DRG bonus
+ Hospitals performing below 9th and 10th decile baseline levels, DRG payments reduced 1% and 2%, respectively
Medicare Looks for Ways to Boost Quality Care Comments Sought on New Plan for Quality Improvement Organizations, Centers for Medicare & Medicare Services (CMS), Accessed through www.cms.hhs.gov.
* CMS quality incentives
o CMS consumer website
+ Beginning in 4/05, hospital quality data available at www.HospitalCompare.hhs.gov or 1-800-MEDICARE
o Data indicators16
+ In 2006, hospitals reporting quality data to Medicare receive 3.7% increase in inpatient payments
+ Non-reporters receive 3.3% increase
+ Data covers 10 quality indicators for cardiology
+ Plans are to expand into other disciplines
and more in this presentation
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Principles of Radiation Oncology
by
Michael Underbrink, MD
Anna Pou, MD
Introduction
* Increasing use for head and neck cancer
* Combined or as single modality
* Outline basic principles, radiobiology
* General treatment approach
* Common complications
Radiation Physics
* Basis – ionizing particles interact with cellular molecules
* Relies on transfer of energy created by secondary charged particles (usually electrons)
* Break chemical bonds
* External beam vs. Brachytherapy
* Radiant energy is discrete yet random
External Beam Irradiation
* Dual-energy linear accelerators generate:
o Low energy megavoltage x-rays (4-6 MeV)
o High energy x-rays (15-20 MeV)
o Photon energy
* Particle Radiation (electrons, protons, neutrons)
* Photon therapy advantages
o Skin sparing, penetration, beam uniformity
* Head and Neck sites – 4-6 MeV x-ray or Co60 gamma ray radiation
External Beam Irradiation
Brachytherapy
* Radioactive source in direct contact with tumor
o Interstitial implants, intracavitary implants or surface molds
* Greater deliverable dose
* Continuous low dose rate
* Advantage for hypoxic or slow proliferators
* Shorter treatment times
Brachytherapy
* Limitations
o Tumor must be accessible
o Well-demarcated
o Cannot be only modality for tumors with high risk of regional lymph node metastasis
Radiobiology
* Ionizing radiation ejects an electron from a target molecule
* Distributed randomly within cell
* Double-strand DNA breaks – lethal
* Cell death: no longer able to undergo unlimited cell division
* Direct vs. Indirect injury (free radicals – O2)
* Inadequate cellular repair mechanisms implied
Radiobiology
* Random cell death
o Deposition of energy & injury is random event
o Same proportion of cells is damaged per dose
o 100 to 10 cell reduction = 106 to 105 cell reduction
o Larger tumors require more radiation
o 105 cells = nonpalpable
o Applies to normal tissue also
* Therapeutic advantage – 4 R’s of radiobiology
4 R’s of radiation biology
* Repair of cellular damage
* Reoxygenation of the tumor
* Redistribution within the cell cycle
* Repopulation of cells
Repair of sublethal injury
* Sublethal injury – cells exposed to sparse ionization fields, can be repaired
* Killing requires greater total dose when given in several fractions
* Most tissue repair in 3 hours, up to 24 hours
* Allows repair of injured normal tissue, potential therapeutic advantage over tumor cells
* Radioresistance – melanoma?
Reoxygenation
* Oxygen stabilizes free radicals
* Hypoxic cells require more radiation to kill
* Hypoxic tumor areas
o Temporary vessel constriction from mass
o Outgrow blood supply, capillary collapse
* Tumor shrinkage decreases hypoxic areas
* Reinforces fractionated dosing
* Hypoxic cell radiosensitizers, selective chemo
Redistribution
* Cell cycle position sensitive cells
* S phase – radioresistant
* G2 phase delay = increased radioresistance
* RAD9 gene mutation – radiosensitive yeast
* H-ras and c-myc oncogenes - G2 delay
* Fractionated XRT redistributes cells
* Rapid cycling cells more sensitive (mucosa, skin)
* Slow cyclers (connective tissue, brain) spared
Repopulation
* Increased regeneration of surviving fraction
* Rapidly proliferating tumors regenerate faster
* Determines length and timing of therapy course
* Regeneration (tumor) vs. Recuperation (normal)
* Reason for accelerated treatment schedules
* Reason against:
o Treatment delay
o Protracted XRT, split course XRT (designed delay)
Dose-Response Relations
* Control probability variables
o Tumor size
o XRT dose
* Favorable response curves
o Small, well-vascularized tumors
o Homogeneous tumors
* Unfavorable response curves
o Large, bulky tumors (hypoxia)
o Heterogeneous, variable cell numbers
* Normal tissue injury risk increases with XRT dose (size of tumor)
Fractionation Schedules
* Conventional
o 1.8 to 2.0 Gy given 5 times/week
o Total of 6 to 8 weeks
o Effort to minimize late complications
* Accelerated fractionation
o 1.8 to 2.0 Gy given bid/tid
o Similar total dose (less treatment time)
o Minimize tumor repopulation (increase local control)
o Tolerable acute complications (increased)
* Hyperfractionation
o 1.0 to 1.2 Gy bid/tid, 5 times/week
o Similar total treatment time (increased total dose)
o Increases total dose
o Potentially increases local control
o Same rates of late complications
o Increased acute reactions
Treatment Principles
* Size and location of primary
* Presence/absence and extent/incidence of regional or distant metastasis
* General condition of patient
* Early stage cancers
o Surgery alone = XRT alone
o Treatment choice depends on functional deficits
* Late stage – usually combination of treatments
* Surgical salvage of primary radiation failures is better than radiation salvage of surgical failure
* Explains rationale behind organ preservation strategies
* XRT tumor cell killing is exponential function
o Dose required for tumor control is proportional to the logarithm of the number of viable cells in the tumor
Shrinking field technique
* Initial dose = 45 to 50 Gy (4.5 to 5.0 weeks)
o Given through large portals
o Covers areas of possible regional metastasis and primary
* Second dose = 15 to 25 Gy (1.5 to 2.5 weeks)
o Boost field (gross tumor and small margin)
o Total dose of 60 to 75 Gy in 6 to 7.5 weeks
* Boost dose = 10 to 15 Gy
o Massive tumors
o Second field reduction at 60 to 65 Gy
o Total of 7 to 8 weeks
Combined Modalities
* Surgery and XRT complement each other
* Surgery – removes gross tumor (bulky tumors are more difficult to control with XRT)
* XRT – effective for microscopic disease, better with exophytic tumors than ulcerative ones (Surgical failures may leave subclinical disease)
* Combining treatments counteracts limitations
* Pre or Post-operative XRT
Preoperative XRT
* Advantages
o Unresectable lesions may become resectable
o Extent of surgical resection diminished
o Smaller treatment portals
o Microscopic disease more radiosensitive (blood supply)
o Decreased risk of distant metastasis from surgical manipulation?
* Disadvantages
o Decreased wound healing
o Decreased safe dose (45 Gy in 4.5 weeks eradicates subclinical disease in 85% to 90% of patients)
* Advantages
o Better surgical staging
o Greater dose can be given safely (60 to 65 Gy in 6 to 7 weeks)
o Total dose can be based on residual tumor burden
o Surgical resection is easier
o Tissue heals better
* Disadvantages
o Distant metastasis by manipulation?
o Delay in postoperative treatment if healing problems (poorer results if delayed more than 6 weeks)
Complications
* Acute Tissue Reactions
* Late Tissue Reactions
Acute Toxicity
* Time onset depends on cell cycling time
* Mucosal reactions – 2nd week of XRT
* Skin reactions – 5th week
* Generally subside several weeks after completion of treatment
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