Explosions in Oncology'

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Explosions in Oncology.

• A brief history of Oncology and an update on the
  state of the art.

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Lone Star Oncology

• Brian J. Shimkus, M.D.
• Medical Oncology/Hematology
• 11044 Research Blvd. Suite D-400
• Austin, TX 78759
• [phone]

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Bari, Italy
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Origins of Oncology

• Oldest known tumor registry dates back to
  300-1500 B.C.
• Egyptians documented survival characteristics of
  women with breast and axillary masses.

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Classification

• Hippocrates 460-370 B.C.
• First to use classification systems to predict
  outcomes.
• First to differentiate benign vs. malignant
  tumors.

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Karkinos

• Greek for Crab
• Malignant tumor vasculature reminded Hippocrates
  of crab claws.
• Translation into early English Carcinos

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The Father of Medical Oncology

• Galen 2nd Century A.D.
• Credited with the observation that Cancer is
  incurable
• The Galenic period persisted for over 1500 years

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Oncologic Epidemiology

• John Hill 1761
• Caution Against Immoderate Use of Snuff
• First to recognize a cause and effect
  relationship between the environment and cancer.

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Surgical Oncology

• John Hunter, M.D.
• Cancer can be cured if it is mobile
• Dr. Hunter described the first curative cancer
  surgery.
• This likely represents the first (rudimentary)
  staging system.

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The century of the Surgeon
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Advances in Surgery

• Rapid advancement in the art of surgery is
  largely due to the invention of anesthesiology in
  1846.
• Allowed refinement in technique and more thorough
  procedures.

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Fathers of Surgical Oncology

• W. Halstead, M.D.
• Bilroth, M.D.
• Hunter, M.D.

• Radical Mastectomy
• Gastro-intestinal surgery
• General Surgery

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Hormonal Therapy
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Pioneers

• Thomas Beatson, M.D. 1878
• Described how oopherectomy in nursing rabbits
  will cease lactation.
• Also noted that oopherectomy in humans often
  reverses metastatic breast cancer.
• This technique is still used as a treatment
  modality today.

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Pioneers

• Charles Huggens, M.D. 1930
• Orchiectomy will stop the pain of metastatic
  prostate cancer and shrink the primary tumor.
• This technique is still widely used today in
  Europe.

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Back to Bari

• 725pm 12/2/1943
• Seaport of Bari is
• attacked by the German Luftwaffe
• A mysterious explosion occurs and the S.S. John
  Harvey disappears in a cloud of garlic smoke.

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Sulfa-Mustard Gas

• Thousands were killed or injured in the attack.
  Survivors developed severe skins burns, eye
  irritation and many eventually died of anemia,
  bleeding and infections.
• Churchill orders all death certificates changed
  to hostile fire.
• Years later physicians reviewed the medical
  records and discovered that mustard gas leads to
  bone marrow failure.

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Cytotoxic Chemotherapy

• Intravenous nitrogen mustard became widely used
  as the first treatment for hematopoetic
  malignancies and still forms the backbone of
  treatment Hodgkins Disease.

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1940s-2000

• 1950s 5-FU and antimetabolites
• 1970s Alkylating agents and Anthracyclines
• 1980s-90s Taxanes and the dawn of
  biotherapy.
• Late 1990s and early 2000s Unlocking key
  mechanisms of cell cycle regulation and
  tumorogenisis.

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The Second Explosion

• Recent Advances in Oncology

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New Therapies

• Cytotoxic Drugs
• VEGF Inhibitors
• EGFR Inhibitors
• Antibodies
• Proteosome Inhibitor
• Molecular Targeted Agents

• Xeloda, Oxaliplatin
• Avastin
• Erbitux, Iressa
• Herceptin, Zevalin
• Velcade
• Gleevec

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Xeloda

• Oral Medication.
• Pro-drug for 5-FU
• Preferentially activated by Thymidylate
  Synthetase in tumor cells.
• Activity in gastrointestinal and breast
  malignacies.
• Radiosensitizer

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Oxaliplatin

• New version of an old theme.
• Typical cytotoxic alkylator with a unique
  activity spectrum and unique side effects.
• This drug is largely responsible for doubling the
  average life expectancy of colon cancer patient.

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Avastin

• VEGF Inhibitor
• Blocks blood Vessel growth and development in
  tumor beds.
• Approved for use in colorectal cancer but will
  likely have a wide range of application.
• Favorable toxicity profile.

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Why Avastin?
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How does it work?
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EGFR InhibitorsErbitux

• Monoclonal antibody directed at the extracellular
  domain of the human EGFR
• Currently approved for use in refractory
  colorectal cancer patient but will likely find
  multiple uses.
• Acceptable toxicity profile.
• Unique mechanism.

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EGFR Pathway
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Mechanism of Action
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EGFR Inhibitor Toxicity
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Iressa

• Small Molecule EGFR inhibitor.
• Similar efficacy and toxicity profile to Erbitux.
• Oral medication for convenient treatment.
• Approved for use in platinum resistant NSCLC.

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RadioimmunotherapyZevalin
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Zevalin

• Targets tumor cells
• Spares most healthy tissue
• Well tolerated
• One-time treatment
• Effective therapy for symptomatic patients

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Why Zevalin?
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Herceptin
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HER-2 Neu

• Human Epidermal Growth-Factor
• Over-expressed on 25 of all human breast
  cancers.
• Rationally developed drug.
• Bench-to-bedside technology.

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Velcade

• Proteosome inhibitor.
• Block the trash removal system.
• Good toxicity profile.
• Early studies suggest a survival advantage even
  in heavily pre-treated patients.

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APEX Survival DataIncluding cross-over patients
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Gleevec

• Created to specifically target the mutation
  leading to CML
• Define the target, create the cure.
• One of the fastest FDA approvals.
• Rationally designed. Rationally studied.

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Mechanism of Gleevec

• Bcr/Abl translocation causes constituative
  activation of a tyrosine kinase and drives
  myeloid cells to division and growth.
• Gleevec targets the bcr/abl translocation sparing
  normal tissue and targeting cancer cells.
• Little toxicity.