Cancer Therapy:Where Have We Been and

Where We are Going from a Radiation Oncologist’s View

John M. Holland, MDCancer Survivors Day

June 9, 2011

Special Thanks to Celine B. Ord, MDOHSU Radiation Medicine Chief Resident

What is cancer?

Significance• Cancer is the2nd leading cause of death in United States• 1,529,560 new cancers and 569,490 deaths in U.S. in 2010

Edwin Smith Papyrus 1600 BC

Origin of the word “Cancer” 460 BC

• Credited to Hippocrates, the Father of Medicine• Derived from term “carcinos” and “carcinoma”• These words often refer to a crab in Greek, because the

finger like projections spreading from a cancer cell suggest a crab.

• Celcus (28- 50BC): Latin- cancer

• Galen in 130- 200AD: Greek- oncos

Renaissance Period• Giovanni Morgagni of Padua 1761

John Hunter 1728-1793

Rudolf Virchow

Causes of Cancer

• Humoral theory of Hippocrates• Lymph theory• Blastema theory• Trauma theory• Parasite theory

DNA

Proto-oncogenes

Tumor suppressor genes

Modern Cancer Treatment

• Surgery• Chemotherapy• Radiation

• Halsted approach-complete resection of tumor and “arms of the crab”

• Modern clinical trials demonstrate that less extensive surgery is equally effective

• Understanding cancer as a disease, better surgical instruments, and combined therapy have enabled surgical progress

• Fiberoptic technology, laparoscopic, endoscopic thorascopic surgeries-less invasive, less morbidity

Evolution of Surgery

Imaging• To diagnose cancer, previously required open

exploratory surgery• Starting in 1970’s. CT, MRI, and PET have

improved diagnosis and staging making exploratory surgery less common.

Chemotherapy

• “Its palliation is a daily task, its cure a fervent hope.”

• William Castle describing leukemia in 1950

• From The Emperor of All Maladies

Chemotherapy for LeukemiaGoodman and Gilman

Nitrogen Mustard for Lymphoma

Chemotherapy for LeukemiaSidney Farber

Antifolates for Acute Leukemia

Multi-modality approach

Cancer Treatment Surgery

Chemotherapy

Radiation

Current Therapies

• Hormonal therapy• Chemotherapy• Immunotherapy• Targeted therapy• Radiation therapy

Hormonal Therapy

Targeted Therapy

Targeted Therapy

Radiation Therapy

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)

Historical Overview

1911 Leukemia reported in radiation workers

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

Historical Overview

Invention of the Medical Linear Accelerator

Karl Brown and Henry KaplanStanford Linear Accelerator Center1950s

Introduction 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

What is radiation? Ionizing Radiation can be divided into 2 types:

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

How does radiation work?

Radiation Damages the Cancer Cell’s DNA

DNA is the critical target of radiation

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 normally.

Radiation survival curve

Therapeutic Ratio

Clinical uses for radiation

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

Curative therapy

Radiation alone

Combined Modality Therapy

Radiation with chemotherapy Radiation and chemotherapy before surgery Radiation and chemotherapy after surgery Radiation alone after surgery

Radiation: Where are we now?

Simulation and Immobilization

X-rays, CT scans, PET scans and MRI’s can be taken for treatment planning purposes in the treatment position

Skin marks, including tattoos, can be placed utilizing laser points matched from simulator to accelerator

Simulation and Immobilization

Treatment planning– Image Fusion

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.

Treatment planning Sophisticated software is used to carefully derive an

appropriate treatment plan for each patient Computerized algorithms enable the treatment plan to

spare as much healthy tissue as possible

Features of a linear accelerator

Gantry and collimator rotation

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

Field may be shaped within the gantry using a multileaf collimator (MLC)

Varian Trilogy Accelerator

Multileaf Collimator– Field Shaping

Types of Delivery

Three-dimensional conformal radiation therapy (3D-CRT) Uses CT or MRI

scans, creating a 3D picture of the tumor

Intensity modulated radiation therapy (IMRT)

A sophisticated form of 3D-CRT

Radiation is broken into many “beamlets,” the intensity of each can be adjusted individually

Image credit: Mayo Clinic

IMRT

IMRT plan in a child with a retroperitoneal rhabdomyosarcoma

Image Guided RadiotherapyIGRT

Using imaging to monitor and modify radiation treatment delivery X-ray (kV or MV), Cone beam CT, Calypso system

IGRT

Bony Anatomy Match

Bony Anatomy Match

Bony Anatomy Match

Bony Anatomy Match

Bony Anatomy Match

Newest Developments

• Calypso™ Real-Time Target Tracking• RapidArc • Stereotactic Body Radiotherapy• Tomotherapy

Calypso

Real Time Target Tracking with Calypso

Can be accomplished through continuous fluoroscopy, usually requiring fiducial implantation

Calypso Medical 4D localization and tracking system “GPS for the body”

Wireless, implantable electromagnetic beacons Utilizes radio frequencies for localization and target

tracking Currently approved for prostate irradiation More applications under study

Calypso

Excitation of beacons sets up distinct magnetic field that decays over time

This field is detected by the array

This process of excitation/sensation is repeated as needed

Actual size: ~8.5 mm

RapidArc

Stereotactic Body Radiotherapy

SBRT

Tomotherapy

Tomotherapy Conformal Radiotherapy

Radiation Dose Painting

Future Therapies

• Robotic surgery• New targeted therapy• Nanotechnology• Proteomics

Acknowlegements

• Veterans Administration• OHSU Department of Radiation Medicine • Joyce Willison• Mark Deffebach, MD• Rachel Sanborn, MD• Neil Gross, MD• James Cohen, MD• Patricia Curtis• Sarah Han

Congratulations!

Thank you