Cancer Therapy:Where Have We Been and Where We are Going from a Radiation Oncologist’s View<br />John M. Holland, MD<br />...
Special Thanks to Celine B. Ord, MDOHSU Radiation Medicine Chief Resident<br />
What is cancer?<br />
Significance<br />   Cancer is the2nd leading cause of death in United States<br />1,529,560 new cancers and 569,490 death...
Edwin Smith Papyrus 1600 BC <br />
Origin of the word “Cancer” 460 BC<br />Credited to Hippocrates, the Father of Medicine<br />Derived from term “carcinos” ...
Renaissance Period<br />Giovanni Morgagni of Padua 1761<br />
John Hunter 1728-1793<br />
Rudolf Virchow<br />
Causes of Cancer	<br />Humoral theory of Hippocrates<br />Lymph theory<br />Blastema theory<br />Trauma theory<br />Parasi...
DNA<br />Proto-oncogenes<br />Tumor suppressor genes<br />
Modern Cancer Treatment	<br />Surgery<br />Chemotherapy<br />Radiation<br />
Halsted approach-complete resection of tumor and “arms of the crab”<br />Modern clinical trials demonstrate that less exte...
Imaging	<br />To diagnose cancer, previously required open exploratory surgery<br />Starting in 1970’s. CT, MRI, and PET h...
Chemotherapy<br />“Its palliation is a daily task, its cure a fervent hope.”<br />William Castle describing leukemia in 19...
Chemotherapy for LeukemiaGoodman and Gilman<br />Nitrogen Mustard for Lymphoma<br />
Chemotherapy for LeukemiaSidney Farber<br />Antifolates for Acute Leukemia<br />
Multi-modality approach<br />
Current Therapies<br />Hormonal therapy<br />Chemotherapy<br />Immunotherapy<br />Targeted therapy<br />Radiation therapy<...
Hormonal Therapy<br />
Targeted Therapy<br />
Targeted Therapy<br />
Radiation Therapy<br />
Historical Overview<br /><ul><li>1895  Roentgen discovers x-rays
1896  Becquerel discovers radioactive emissions from uranium compounds
1897  First reported use of x-rays to treat cancer
1898  Curies discover radium and polonium
1899  First reported cure of cancer (basal cell)</li></li></ul><li>Historical Overview<br /><ul><li>1911 Leukemia reported...
1928  First international guidelines for radiation safety
1945 Atomic bombs in Hiroshima and Nagasaki
1953 Watson and Crick discover structure of DNA; first linear accelerator made to treat patients</li></li></ul><li>
Invention of the Medical Linear Accelerator<br />Karl Brown and Henry Kaplan<br />Stanford Linear Accelerator Center<br />...
Introduction<br /><ul><li>Radiation has been an effective tool for treating cancer for over 100 years
More than 60 percent of patients diagnosed with cancer will receive radiation therapy as part of their treatment
Today, more than 1 million cancer patients are treated annually with radiation
Radiation oncologists are cancer specialists who manage cancer patients using radiation for cure or palliation</li></li></...
Electromagnetic Waves (Photons)
Gamma Rays
Emitted from a radioactive source
Cobalt treatment machine (Cobalt is the radioactive source in the head of the machine)
X-rays
Photons are generated by a linear accelerator
Particles
Protons, neutrons, electrons, heavy pi mesons, alpha particles</li></li></ul><li>How does radiation work?<br />Radiation D...
DNA is the critical target of radiation<br /><ul><li>Radiation can cause both SSBs and DSBs.
Double strand breaks kill cancer cells because they lead to chromosomal aberrations which prevent the cell from dividing n...
Therapeutic Ratio<br />
Clinical uses for radiation<br /><ul><li>Therapeutic radiation serves two major functions
To cure cancer
Destroy tumors that have not spread
Reduce the risk that cancer will return after surgery or chemotherapy
To reduce or palliate symptoms
Shrink tumors affecting quality of life, e.g., a lung tumor causing shortness of breath
Relieve pain by reducing the size of a tumor</li></li></ul><li>Curative therapy<br /><ul><li>Radiation alone</li></ul>Comb...
Radiation and chemotherapy before surgery
Radiation and chemotherapy after surgery
Radiation alone after surgery</li></li></ul><li>Radiation: Where are we now?<br />
Simulation and Immobilization<br /><ul><li>X-rays, CT scans, PET scans and MRI’s can be taken for treatment planning purpo...
Skin marks, including tattoos, can be placed utilizing laser points matched from simulator to accelerator</li></li></ul><l...
Treatment planning– Image Fusion<br /><ul><li>Fusion with MRI allows for better tumor definition.
Fusion with PET allows for better tumor localization.
Both allow better targeting of the tumor and less treatment to normal tissues.</li></li></ul><li>
Treatment planning<br /><ul><li>Sophisticated software is used to carefully derive an appropriate treatment plan for each ...
Computerized algorithms enable the treatment plan to spare as much healthy tissue as possible</li></li></ul><li>Features o...
Table rotates on pedestal and moves vertically, horizontally, and laterally
Table limit is now over 400 pounds
Machine can produce one or two energies of photons and multiple energies of electrons
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Holland survivors day 2011

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  • Pulitzer Prize winner for 2011 Nonfiction“Biography” of cancer
  • Normal body cells grow, divide, and die in an orderly fashion.Cancer cells grow out of control, and don’t adhere to the orderly process. They grow out of control due to damage in their DNA, which can result from environmental effects (cigarette smoking), but often there is no clear cause for DNA damage.
  • Oldest description of tumor. “Cancer” not used.Discovered in Egypt, dating to 1600BC.Describes 8 cases of breast cancer, including 1 in a man.Treated with cauterization, called a “fire drill”.Notably, the writing says, “There is no treatment”.
  • “Carcinos”, “Carcinoma” to describe tumors.These words often refer to a crab in Greek, because the finger like projections spreading from a cancer cell suggest a crab.
  • 1st to do autopsies to correlate patient’s illness to pathological findings after deathLaid foundation for scientific oncology
  • Suggested that if tumors had not invaded nearby tissue, and the tissue was “moveable”There was no impropriety in removing it.Detailed surgical experience in Portugal and Channel Islands as army surgeon.A century later, development of anesthesia allowed surgery to flourish.RM developed.
  • Founder of cellular pathology. Allowed correlation of microscopic pathology to clinical course of illness.Allowed removed tissues to be examined, and to determine whether the tumor is completely removed.
  • Humoral: blood, phlegm, yellow &amp; black bileLymph: fermenting/degenerating lymphBlastema: cancer cells arise from blastema (budding cells) between normal tissuesTrauma: Parasite:
  • Watson &amp; Crick discovered double helix 1953, and received Nobel Prize in 1962. Found that damage to DNA by chemicals and RT, and introduction of new DNA sequences by viruses lead to development of cancer.Proto-oncogenes: gas pedalTumor suppressor genes: brake pedal
  • Hippocrates and Galen pronounced people incurable at initial diagnosis of cancer, though Galen did make an observation that if an early tumor was completely removed, it might be surgically cured.
  • Two pharmacologists, Louis S. Goodman and Alfred Gilman, were recruited by the United States Department of Defense to investigate potential therapeutic applications of chemical warfare agents. A year into the start of their research a German air raid in Bari, Italy led to the exposure of more than one thousand people to the SS John Harvey&apos;s secret cargo composed of mustard gasbombs. Dr. Stewart Francis Alexander, a Lieutenant Colonel who was an expert in chemical warfare, was subsequently deployed to investigate the aftermath. Autopsies of the victims suggested that profound lymphoid and myeloid suppression had occurred after exposure. In his report Dr. Alexander theorized that since mustard gas all but ceased the division of certain types of Somatic cells whose nature it was to divide fast, it could also potentially be put to use in helping to suppress the division of certain types of cancerous cells
  • Shortly after World War II, a second approach to drug therapy of cancer began. Sidney Farber, a pathologist at Harvard Medical School, studied the effects of folic acid on leukemia patients. Folic acid, a vitamin crucial for DNA metabolism (he did not know the significance of DNA at that time), had been discovered by Lucy Wills, when she was working in India, in 1937. It seemed to stimulate the proliferation of acute lymphoblastic leukemia (ALL) cells when administered to children with this cancer. In one of the first examples of rational drug design (rather than accidental discovery), in collaboration with Harriett Kilte and YellapragadaSubbarao of Lederle Laboratories, Farber used folate analogues. These analogues — first aminopterin and then amethopterin (now methotrexate) were antagonistic to folic acid, and blocked the function of folate-requiring enzymes. When administered to children with ALL in 1948, these agents became the first drugs to induce remission in children with ALL.
  • Immunotherapy: rituxan: monoclonal AbHerceptin.Targeted: influence factors that control growth, division, spread of cancer cells. -gefinitib. -imatinib -cetuximab
  • Willhelm Conrad Roentgen and the Xray of his wife’s hand
  • Supervoltagexray machine (betatron) aimed at a patient with bladder cancer at the Lila Motley Radiation Clinic of New York’s Hospital for Joint Diseases
  • The primary effect of radiation on cancer is to damage the DNASome of this occurs via a direct interaction of the radiation with DNAMost of this occurs by ionizing radiation interacting with surrounding water, creating free radicals that then interact and damage DNA
  • Cells can repair radiation damage-especially SSBsDamage to DNA can cause MUTATIONS too
  • As radiation dose increases, cancer cell survival decreases
  • In making treatment decisions in oncology, it is important to examine the therapeutic ratio or do the benefits of the therapy outweigh the risks of toxicity?In radiation oncology, to determine the therapeutic ratio one must know the likelihood of controlling a tumor with a certain dose and the likelihood of producing a complication with that same dose.
  • Increasingly, patients are treated with a combination of therapies, e.g. chemotherapy and radiation therapy or chemotherapy, surgery and radiation therapy. The drugs given and sequence of therapies is determined by the disease, the stage of the disease and the comorbidities of the patient.The reasons for combining therapies include improvement in survival, decrease in toxicity, and improved chances for organ preservation.
  • Simulation allows the patient to be placed into the treatment position using any number of immobilization devices
  • Immobilization ensures that treatment set up is reproducible and stable for our day to day therapy
  • PET allows “functional” imaging using glucose metabolism as a biologic marker of cancer
  • We spend a lot of the time in dark rooms much like our diagnostic radiology brothers
  • Physicists and dosimetrists work together to create the optimal treatment plan for each individual patient
  • Image Guidance Before Each Treatment
  • uses hundreds of small radiation beams of varying intensities to precisely radiate a tumor and spare normal tissues. The radiation intensity of each beam is controlled, and the beam shape changes hundreds of times during each treatment. As a result, the radiation dose bends around healthy tissues in a way not possible with other techniques.
  • Each beam angle is segmented so that the entire tumor is not treated with each segment but the intensity of the dose can be varied rapidly across a volume.Allows for rapid dose fall off when a target is near a critical structure, especially when the target is concave.
  • IMRT to treat prostate cancer and spare the rectum
  • Image Guidance gives us precision by allowing us to fine tune position prior to each radiation treatment
  • kV-kV image guidance
  • Volumetric modulated arc therapyRapidArc is a volumetric arc therapy that delivers a precisely sculpted 3D dose distribution with a single 360-degree rotation of the linear accelerator gantry. It is made possible by a treatment planning algorithm that simultaneously changes three parameters during treatment:rotation speed of the gantry shape of the treatment aperture using the movement of multileaf collimator leaves delivery dose rate. Volumetric modulated arc therapy differs from existing techniques like helical IMRT or intensity-modulated arc therapy (IMAT) because it delivers dose to the whole volume, rather than slice by slice. And the treatment planning algorithm ensures the treatment precision, helping to spare normal healthy tissue.
  • volumetric arc therapy. Delivers precisely sculpted 3D dose distribution with a single 360-degree rotation of the gantry. Treatment planning algorithm that simultaneously changes three parameters during treatment: 1) rotation speed of the gantry 2)shape of the treatment aperture using the movement of multileaf collimator leaves 3) delivery dose rate. delivers dose to the whole volume, rather than slice by slice
  • Our Tomotherapy Unit at OHSU
  • Tomotherapy can deliver radiotherapy to tumors and spare critical normal structures like brain, bowel, spinal cord and lung
  • Nanotechnology: engineering tiny particles for diagnostics to localize tumors or to deliver drugsProteomics: comparing relative amounts of many proteins may provide info about cancers for screening. Early results in lung/colorectal promising.
  • Transcript of "Holland survivors day 2011"

    1. 1. Cancer Therapy:Where Have We Been and Where We are Going from a Radiation Oncologist’s View<br />John M. Holland, MD<br />Cancer Survivors Day<br />June 9, 2011<br />
    2. 2. Special Thanks to Celine B. Ord, MDOHSU Radiation Medicine Chief Resident<br />
    3. 3.
    4. 4. What is cancer?<br />
    5. 5. Significance<br /> Cancer is the2nd leading cause of death in United States<br />1,529,560 new cancers and 569,490 deaths in U.S. in 2010<br />
    6. 6. Edwin Smith Papyrus 1600 BC <br />
    7. 7. Origin of the word “Cancer” 460 BC<br />Credited to Hippocrates, the Father of Medicine<br />Derived from term “carcinos” and “carcinoma”<br />These words often refer to a crab in Greek, because the finger like projections spreading from a cancer cell suggest a crab.<br />Celcus (28- 50BC): Latin- cancer <br />Galen in 130- 200AD: Greek- oncos<br />
    8. 8. Renaissance Period<br />Giovanni Morgagni of Padua 1761<br />
    9. 9. John Hunter 1728-1793<br />
    10. 10. Rudolf Virchow<br />
    11. 11. Causes of Cancer <br />Humoral theory of Hippocrates<br />Lymph theory<br />Blastema theory<br />Trauma theory<br />Parasite theory<br />
    12. 12. DNA<br />Proto-oncogenes<br />Tumor suppressor genes<br />
    13. 13. Modern Cancer Treatment <br />Surgery<br />Chemotherapy<br />Radiation<br />
    14. 14. Halsted approach-complete resection of tumor and “arms of the crab”<br />Modern clinical trials demonstrate that less extensive surgery is equally effective<br />Understanding cancer as a disease, better surgical instruments, and combined therapy have enabled surgical progress<br />Fiberoptic technology, laparoscopic, endoscopic thorascopic surgeries-less invasive, less morbidity<br />Evolution of Surgery<br />
    15. 15. Imaging <br />To diagnose cancer, previously required open exploratory surgery<br />Starting in 1970’s. CT, MRI, and PET have improved diagnosis and staging making exploratory surgery less common.<br />
    16. 16. Chemotherapy<br />“Its palliation is a daily task, its cure a fervent hope.”<br />William Castle describing leukemia in 1950<br />From The Emperor of All Maladies<br />
    17. 17. Chemotherapy for LeukemiaGoodman and Gilman<br />Nitrogen Mustard for Lymphoma<br />
    18. 18. Chemotherapy for LeukemiaSidney Farber<br />Antifolates for Acute Leukemia<br />
    19. 19. Multi-modality approach<br />
    20. 20. Current Therapies<br />Hormonal therapy<br />Chemotherapy<br />Immunotherapy<br />Targeted therapy<br />Radiation therapy<br />
    21. 21. Hormonal Therapy<br />
    22. 22. Targeted Therapy<br />
    23. 23. Targeted Therapy<br />
    24. 24. Radiation Therapy<br />
    25. 25. Historical Overview<br /><ul><li>1895 Roentgen discovers x-rays
    26. 26. 1896 Becquerel discovers radioactive emissions from uranium compounds
    27. 27. 1897 First reported use of x-rays to treat cancer
    28. 28. 1898 Curies discover radium and polonium
    29. 29. 1899 First reported cure of cancer (basal cell)</li></li></ul><li>Historical Overview<br /><ul><li>1911 Leukemia reported in radiation workers
    30. 30. 1928 First international guidelines for radiation safety
    31. 31. 1945 Atomic bombs in Hiroshima and Nagasaki
    32. 32. 1953 Watson and Crick discover structure of DNA; first linear accelerator made to treat patients</li></li></ul><li>
    33. 33. Invention of the Medical Linear Accelerator<br />Karl Brown and Henry Kaplan<br />Stanford Linear Accelerator Center<br />1950s<br />
    34. 34. Introduction<br /><ul><li>Radiation has been an effective tool for treating cancer for over 100 years
    35. 35. More than 60 percent of patients diagnosed with cancer will receive radiation therapy as part of their treatment
    36. 36. Today, more than 1 million cancer patients are treated annually with radiation
    37. 37. Radiation oncologists are cancer specialists who manage cancer patients using radiation for cure or palliation</li></li></ul><li>What is radiation?<br /><ul><li>Ionizing Radiation can be divided into 2 types:
    38. 38. Electromagnetic Waves (Photons)
    39. 39. Gamma Rays
    40. 40. Emitted from a radioactive source
    41. 41. Cobalt treatment machine (Cobalt is the radioactive source in the head of the machine)
    42. 42. X-rays
    43. 43. Photons are generated by a linear accelerator
    44. 44. Particles
    45. 45. Protons, neutrons, electrons, heavy pi mesons, alpha particles</li></li></ul><li>How does radiation work?<br />Radiation Damages the Cancer Cell’s DNA<br />
    46. 46. DNA is the critical target of radiation<br /><ul><li>Radiation can cause both SSBs and DSBs.
    47. 47. Double strand breaks kill cancer cells because they lead to chromosomal aberrations which prevent the cell from dividing normally.</li></li></ul><li>Radiation survival curve<br />
    48. 48. Therapeutic Ratio<br />
    49. 49. Clinical uses for radiation<br /><ul><li>Therapeutic radiation serves two major functions
    50. 50. To cure cancer
    51. 51. Destroy tumors that have not spread
    52. 52. Reduce the risk that cancer will return after surgery or chemotherapy
    53. 53. To reduce or palliate symptoms
    54. 54. Shrink tumors affecting quality of life, e.g., a lung tumor causing shortness of breath
    55. 55. Relieve pain by reducing the size of a tumor</li></li></ul><li>Curative therapy<br /><ul><li>Radiation alone</li></ul>Combined Modality Therapy<br /><ul><li>Radiation with chemotherapy
    56. 56. Radiation and chemotherapy before surgery
    57. 57. Radiation and chemotherapy after surgery
    58. 58. Radiation alone after surgery</li></li></ul><li>Radiation: Where are we now?<br />
    59. 59. Simulation and Immobilization<br /><ul><li>X-rays, CT scans, PET scans and MRI’s can be taken for treatment planning purposes in the treatment position
    60. 60. Skin marks, including tattoos, can be placed utilizing laser points matched from simulator to accelerator</li></li></ul><li>Simulation and Immobilization<br />
    61. 61. Treatment planning– Image Fusion<br /><ul><li>Fusion with MRI allows for better tumor definition.
    62. 62. Fusion with PET allows for better tumor localization.
    63. 63. Both allow better targeting of the tumor and less treatment to normal tissues.</li></li></ul><li>
    64. 64. Treatment planning<br /><ul><li>Sophisticated software is used to carefully derive an appropriate treatment plan for each patient
    65. 65. Computerized algorithms enable the treatment plan to spare as much healthy tissue as possible</li></li></ul><li>Features of a linear accelerator<br /><ul><li>Gantry and collimator rotation
    66. 66. Table rotates on pedestal and moves vertically, horizontally, and laterally
    67. 67. Table limit is now over 400 pounds
    68. 68. Machine can produce one or two energies of photons and multiple energies of electrons
    69. 69. Field may be shaped within the gantry using a multileaf collimator (MLC)</li></li></ul><li>Varian Trilogy Accelerator<br />
    70. 70. Multileaf Collimator– Field Shaping<br />
    71. 71. Types of Delivery<br /><ul><li>Three-dimensional conformal radiation therapy (3D-CRT)
    72. 72. Uses CT or MRI scans, creating a 3D picture of the tumor </li></li></ul><li>Intensity modulated radiation therapy (IMRT)<br /><ul><li>A sophisticated form of 3D-CRT
    73. 73. Radiation is broken into many “beamlets,” the intensity of each can be adjusted individually</li></ul>Image credit: Mayo Clinic<br />
    74. 74. IMRT<br />IMRT plan in a child with a retroperitoneal rhabdomyosarcoma<br />
    75. 75.
    76. 76. Image Guided RadiotherapyIGRT<br /><ul><li>Using imaging to monitor and modify radiation treatment delivery
    77. 77. X-ray (kV or MV), Cone beam CT, Calypso system</li></li></ul><li>IGRT<br />
    78. 78. Bony Anatomy Match<br />
    79. 79. Bony Anatomy Match<br />
    80. 80. Bony Anatomy Match<br />
    81. 81. Bony Anatomy Match<br />
    82. 82. Bony Anatomy Match<br />
    83. 83. Newest Developments<br />Calypso™ Real-Time Target Tracking<br />RapidArc<br />Stereotactic Body Radiotherapy<br />Tomotherapy<br />
    84. 84. Calypso<br />
    85. 85. Real Time Target Tracking with Calypso<br /><ul><li>Can be accomplished through continuous fluoroscopy, usually requiring fiducial implantation
    86. 86. Calypso Medical 4D localization and tracking system “GPS for the body”
    87. 87. Wireless, implantable electromagnetic beacons
    88. 88. Utilizes radio frequencies for localization and target tracking
    89. 89. Currently approved for prostate irradiation
    90. 90. More applications under study</li></li></ul><li>Calypso<br /><ul><li>Excitation of beacons sets up distinct magnetic field that decays over time
    91. 91. This field is detected by the array
    92. 92. This process of excitation/sensation is repeated as needed</li></ul>Actual size: ~8.5 mm<br />
    93. 93. RapidArc<br />
    94. 94. Stereotactic Body <br />Radiotherapy <br />SBRT<br />
    95. 95. Tomotherapy<br />
    96. 96. Tomotherapy Conformal Radiotherapy<br />Radiation Dose Painting<br />
    97. 97. Future Therapies<br />Robotic surgery<br />New targeted therapy<br />Nanotechnology<br />Proteomics <br />
    98. 98. Acknowlegements<br />Veterans Administration<br />OHSU Department of Radiation Medicine <br />Joyce Willison<br />Mark Deffebach, MD<br />Rachel Sanborn, MD<br />Neil Gross, MD<br />James Cohen, MD<br />Patricia Curtis<br />Sarah Han<br />
    99. 99. Congratulations!<br />
    100. 100. Thank you<br />
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