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Seymour H. Levitt • James A. Purdy
Carlos A. Perez • Philip Poortmans
Editors

Technical Basis of
Radiation Therapy
Practical Clinical Applications

Fifth Edition

123
Seymour H. Levitt, MD, DSc. Carlos A. Perez, MD
Department of Oncol-Pathol Department of Radiation Oncology
Karolinska Institutet Washington University Medical Center
Stockholm 4511 Forest Park Boulevard
Sweden St. Louis, MO 63108
e-mail: [email protected] USA
e-mail: [email protected]
James A. Purdy, Ph.D.
Department of Radiation Oncology Philip Poortmans, Ph.D.
University of California Department of Radiation Oncology
Davis Medical Center Institute Verbeeten
4501 X Street Brugstraat 10
Sacramento, CA 95817 Tilburg, 5042 SB
USA The Netherlands
e-mail: [email protected] e-mail: [email protected]

ISSN 0942-5373
ISBN 978-3-642-11571-4 e-ISBN 978-3-642-11572-1
DOI 10.1007/978-3-642-11572-1
Springer Heidelberg Dordrecht London New York

Library of Congress Control Number: 2011941621

Ó Springer-Verlag Berlin Heidelberg 2012

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Contents

Part I Basic Concepts in Radiation Oncology

Practical Time–Dose Evaluations, or How to Stop Worrying

and Learn to Love Linear Quadratics . . . . . . . . . . . . . . . . . . . . . . . . . 3
Jack F. Fowler

Radiobiology of Stereotactic Radiosurgery and Stereotactic Body

Radiation Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
Chang W. Song, Heonjoo Park, Robert J. Griffin, and Seymour H. Levitt

Imaging in Radiation Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63

Cynthia Ménard, Ursula Nestle, and David Jaffray

Physics of Radiotherapy Planning and Delivery . . . . . . . . . . . . . . . . . . 85

James A. Purdy, Philip Poortmans, Carlos A. Perez, and Seymour H. Levitt

Simulation in the Determination and Definition of Treatment

Volume and Treatment Planning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133
Sasa Mutic, Mary Coffey, James A. Purdy, Jeff M. Michalski,
and Carlos A. Perez

Clinical Applications of High-Energy Electrons . . . . . . . . . . . . . . . . . . 157

Bruce J. Gerbi, Youlia M. Kirova, and Roberto Orecchia

Proton Therapy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197

Nancy Price Mendenhall and Zuofeng Li

Physical, Biological and Clinical Background for the Development

of Light Ion Therapy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 219
Anders Brahme

Three-Dimensional Treatment Planning and Conformal Therapy . . . . . 253

James A. Purdy, Philip Poortmans, and Carlos A. Perez

Linac-Based Image Guided Intensity Modulated Radiation Therapy . . . 275

Ruijiang Li, Paul Keall, and Lei Xing

v
vi Contents

Tomotherapy Image Guided Radiation Therapy. . . . . . . . . . . . . . . . . . 313

Walter H. Grant III, E. Brian Butler, and Dirk Verellen

Robotic Image Guided Radiation Therapy . . . . . . . . . . . . . . . . . . . . . . 325

Rodney E. Wegner, Dwight E. Heron, Arlan H. Mintz, and M. Saiful Huq

Cranial Stereotactic Radiosurgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . 335

Joseph R. Simpson, Robert E. Drzymala, Keith M. Rich,
and Brigitta G. Baumert

Stereotactic Body Radiotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 363

L. Chinsoo Cho, Valérie Fonteyne, Wilfried DeNeve, Simon S. Lo,
and Robert D. Timmerman

Physics and Clinical Aspects of Brachytherapy. . . . . . . . . . . . . . . . . . . 401

Bruce Thomadsen, Jack Venselaar, and Zuofeng Li

Principles and Clinical Applications of Pulsed Dose

Rate Brachytherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 435
Bethany Anderson, Christine Haie-Meder, and Erik Van Limbergen

Clinical Applications of High-Dose-Rate Brachytherapy . . . . . . . . . . . . 461

Subir Nag and Granger R. Scruggs

Quality Management and Safety in Radiation Oncology . . . . . . . . . . . . 485

James A. Purdy, Eric E. Klein, Philip Poortmans, and Coen Hurkmans

Quality Assurance for Multi-Institutional Clinical Trials . . . . . . . . . . . 531

James A. Purdy and Philip M. Poortmans

Promises and Pitfalls of Health Technology Assessment . . . . . . . . . . . . 549

Yolande Lievens, Peter Dunscombe, and Andre Konski

Part II Clinical Applications

Central Nervous System Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 565

William A. Hall and Walter J. Curran

Head and Neck Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 601

Allen M. Chen and K. S. Clifford Chao

Breast Cancer: Intact and Post Mastectomy . . . . . . . . . . . . . . . . . . . . . 641

Elizabeth S. Bloom, Philip Poortmans, Marianne Aznar,
Thomas A. Buchholz, and Eric A. Strom

Accelerated Partial Breast Irradiation . . . . . . . . . . . . . . . . . . . . . . . . . 685

Ben Wilkinson, Laurie Cuttino, Dorin Todor, and Frank Vicini
Contents vii

Esophageal Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 717

Brian G. Czito and Christopher G. Willett

Cancer of the Lung . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 755

Joe Y. Chang

Cancers of the Colon, Rectum, and Anus . . . . . . . . . . . . . . . . . . . . . . . 777

Jonathan B. Ashman, Matthew D. Callister, Michael G. Haddock,
and Leonard L. Gunderson

Bladder Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 801

Peter Han, Marvin Rotman, Alan R. Schulsinger, Bradley R. Pieters,
Caro C. E. Koning, Floris J. Pos, Maarten C. C. M. Hulshof,
and Philip Poortmans

Radiation Therapy for Cervical Cancer . . . . . . . . . . . . . . . . . . . . . . . . 829

Kathryn E. Dusenbery and Bruce J. Gerbi

Technical Aspects of Radiation Therapy in Endometrial

Carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 855
Higinia R. Cárdenes, David L. Andolino, and Jennifer E. Zook

Vulva . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 889
Carlos A. Perez and Imran Zoberi

Carcinoma of the Vagina. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 917

Higinia R. Cardenes, Jennifer E. Zook, and David L. Andolino

Prostate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 949
Jeff M. Michalski and Thomas Wiegel

Testicular Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1027

Gerard C. Morton and Maria Pearse

Extremity Soft Tissue Sarcoma in Adults . . . . . . . . . . . . . . . . . . . . . . 1041

Karl E. Haglund, Thomas F. DeLaney, David C. Harmon,
Andrew E. Rosenberg, and Francis J. Hornicek

Total Body Irradiation Conditioning Regimens in Stem

Cell Transplantation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1077
Kathryn E. Dusenbery and Bruce J. Gerbi

Radiation Therapy for Hodgkin Lymphoma and

Other Hematopoietic Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1099
Chung K. Lee and Philip Poortmans

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1141
Contributors

Bethany Anderson Department of Human Oncology, University of Wisconsin,

600 Highland Avenue, Madison, WI 53792, USA, e-mail: anderson@humonc.
wisc.edu
David L. Andolino Department of Radiation Oncology, Indiana University
School of Medicine, 535 Barnhill Drive, RT 041, Indianapolis, IN 46202, USA
Jonathan B. Ashman Department of Radiation Oncology, Mayo Clinic Col-
lege of Medicine and Mayo Clinic, 5777 E. Mayo Blvd, Phoenix, AZ 85054,
USA e-mail: [email protected]
Marianne Aznar Department of Radiation Oncology, Rigshospitalet/Copen-
hagen University Hospital, Copenhagen, Denmark
Brigitta G. Baumert Department of Radiation-Oncology (MAASTRO) and
GROW (School for Oncology and Developmental Biology), University
Medical Center Maastricht (MUMC), Maastricht, The Netherlands
Elizabeth S. Bloom Division of Radiation Oncology, The University of Texas
M. D. Anderson Cancer Center, Houston, TX 77030, USA
Anders Brahme Department of Medical Radiation Physics, Karolinska
Institutet, Box 260, 17176 Stockholm, Sweden, e-mail: [email protected]
E. Brian Butler Radiation Oncology, The Methodist Hospital, Houston, TX
77030, USA
Matthew D. Callister Department of Radiation Oncology, Mayo Clinic College
of Medicine and Mayo Clinic, 5777 E. Mayo Blvd, Phoenix, AZ 85054, USA
Higinia R. Cardenes Department of Radiation Oncology, Indiana University
School of Medicine, 535 Barnhill Drive, RT 041, Indianapolis, IN 46202, USA
e-mail: [email protected]
Joe Y. Chang Department of Radiation Oncology, MD Anderson Cancer
Center, Houston, TX, USA, e-mail: [email protected]

ix
x Contributors

Allen M. Chen UC Davis Cancer Center, 4501 X Street, Sacramento, CA, USA,
e-mail: [email protected]
L. Chinsoo Cho Department of Radiation Oncology, University of Minnesota
Medical Center, 420 Delaware St, SE MMC-494, Minneapolis, MN 55455,
USA, e-mail: [email protected]
K. S. Clifford Chao Weill Cornell Radiation Oncology, 622 West 168th Street,
New York, NY 10032, USA
Mary Coffey Discipline of Radiation Therapy, School of Medicine, Trinity
Centre for Health Sciences, St. James’ Hospital, Dublin 8, Ireland
Walter J. Curran Department of Radiation Oncology, Winship Cancer Insti-
tute, Emory University, Atlanta, GA, USA
Laurie Cuttino Department of Radiation Oncology, Massey Cancer Center,
Virginia Commonwealth University, Richmond, VA 23298, USA
Brian G. Czito Department of Radiation Oncology, Duke University Medical
Center, Morris Bldg, Box 3085, Durham, NC 27710, USA, e-mail:
[email protected]
Thomas F. DeLaney Francis H. Burr Proton Therapy Center, Massachusetts
General Hospital, Harvard Medical School, 30 Fruit Street, Boston, MA 02114,
USA
Wilfried DeNeve Department of Radiotherapy-Oncology, Ghent University
Hospital, De Pintelaan 185, 9000 Ghent, Belgium
Robert E. Drzymala Department of Radiation Oncology, Washington
University School of Medicine, 4921 Parkview Place, Campus Box 8224, St.
Louis, MO 63110, USA
Peter Dunscombe Department of Oncology, University of Calgary, Calgary,
AB T2N 1N4, Canada
Kathryn E. Dusenbery Therapeutic Radiology–Radiation Oncology University
of Minnesota Medical School, MMC 494, 420 Delaware St SE, Minneapolis,
MN, 55455, USA, e-mail: [email protected]
Valérie Fonteyne Department of Radiotherapy-Oncology, Ghent University
Hospital, De Pintelaan 185, 9000 Ghent, Belgium
Jack F. Fowler Human Oncology and Medical Physics, Medical School of
University of Wisconsin, Madison, WI, USA; Gray Laboratory, Northwood,
London, UK; 150 Lambeth Road, London SE1 7DF, UK
Bruce J. Gerbi Department of Therapeutic Radiology, Radiation Oncology,
University of Minnesota, Mayo Mail Code 494, 420 Delaware St SE, Minne-
apolis, MN 55455, USA; Therapeutic Radiology–Radiation Oncology,
University of Minnesota Medical School, MMC 494, 420 Delaware St SE,
Minneapolis, MN 55455, USA; Department of Therapeutic Radiology-
Radiation Oncology, University of Minnesota Medical School, MMC 494, 420
Delaware St. S.E, Minneapolis, MN 55455, USA
Contributors xi

Walter H. Grant III Department of Radiology, BCM 360, Baylor College of

Medicine, Houston, TX 77030, USA, e-mail: [email protected]
Robert J. Griffin Department of Therapeutic Radiology-Radiation Oncology,
University of Minnesota, 420 Delaware St. SE, Mayo Mail Code 494,
Minneapolis, MN 55455, USA
Leonard L. Gunderson Department of Radiation Oncology, Mayo Clinic
College of Medicine and Mayo Clinic, 5777 E. Mayo Blvd, Phoenix, AZ 85054,
USA
Michael G. Haddock Department of Radiation Oncology, Mayo Clinic College
of Medicine and Mayo Clinic, 200 2nd St. SW Desk R, Rochester, MN 55905,
USA
Karl E. Haglund Radiation Oncology Branch, National Cancer Institute,
10 Center Drive, Building 10/CRC, Bethesda, MD 20892, USA, e-mail:
[email protected]
Christine Haie-Meder Institut Gustave Roussy, Brachytherapy Unit, 114 rue
Edouard Vaillant, 94800 Villejuif, France, e-mail: [email protected];
[email protected]
William A. Hall Department of Radiation Oncology, Winship Cancer Institute,
Emory University, Atlanta, GA, USA e-mail: [email protected]
Peter Han Department of Radiation Oncology, State University of New York,
Health Science Center at Brooklyn, 450 Clarkson Aven, Box 1211, Brooklyn,
NY 11203-2098, USA, e-mail: [email protected]
David C. Harmon Hematology Oncology, Department of Medicine, Massa-
chusetts General Hospital, Harvard Medical School, Yawkey 7944, 30 Fruit
Street, Boston, MA 02114, USA
Dwight E. Heron Department of Radiation Oncology, University of Pittsburgh
Cancer Institute, 5150 Centre Avenue, #545, Pittsburgh, PA 15232, USA;
Department of Otolaryngology, University of Pittsburgh Cancer Institute,
Pittsburgh, PA, USA
Francis J. Hornicek Orthopedic Oncology, Department of Orthopedic Surgery,
Massachusetts General Hospital, Harvard Medical School, Yawkey 3B, 30
Fruit Street, Boston, MA 02114, USA
Maarten C. C. M. Hulshof Department of Radiation Oncology, Academic
Medical Center/University of Amsterdam, P.O. Box 22660, Z0-214, 1100 DD
Amsterdam, The Netherlands
M. Saiful Huq Department of Radiation Oncology, University of Pittsburgh
Cancer Institute, 5150 Centre Avenue, #545, Pittsburgh, PA 15232, USA
Coen Hurkmans Department of Radiation Oncology, Catharina Hospital,
Eindhoven, The Netherlands
David Jaffray Princess Margaret Hospital, University of Toronto, 610
University Avenue, Toronto, ON, M5G 2M9, Canada
xii Contributors

Paul Keall Radiation Physics Laboratory, University of Sydney, Sydney

Medical School—Central Room 475, Blackburn Building D06, Camperdown
2006, NSW, 3590, Australia
Youlia M. Kirova Department of Radiation Oncology, Institut Curie, 26 Rue
d’Ulm, 75005 Paris, France
Eric E. Klein Department of Radiation Oncology, Washington University
School of Medicine, St. Louis, MI 63110, USA
Caro C. E. Koning Department of Radiation Oncology, Academic Medical
Center/University of Amsterdam, P.O. Box 22660, Z0-214, 1100 DD Amster-
dam, The Netherlands
Andre Konski Department of Radiation Oncology, Wayne State University
School of Medicine, Karmanos Cancer Center, Detroit, MI 48201, USA
Chung K. Lee Department of Therapeutic Radiology–Radiation Oncology,
University of Minnesota, Minneapolis, MN, USA
Seymour H. Levitt Department of Therapeutic Radiation Oncology, University
of Minnesota, Minneapolis, MN 55455, USA; Department of Therapeutic
Radiology-Radiation Oncology, University of Minnesota, 420 Delaware St. SE,
MI 494, Minneapolis, MN, 55455, USA
Zuofeng Li Department of Radiation Oncology, University of Florida Proton
Therapy Institute, University of Florida, Jacksonville, FL 32206, USA;
University of Florida Proton Institute, 2015 North Jefferson Street, Jackson-
ville, FL 32206, USA
Ruijiang Li Department of Radiation Oncology, Stanford University, 875
Blake Wilbur Drive Room G204, Stanford, CA 94305-5847, USA, e-mail:
[email protected]
Yolande Lievens Radiation Oncology Department, Universitaire Ziekenhuizen
Leuven, 3000, Leuven, Belgium, e-mail: [email protected]
Simon S. Lo Department of Radiation Oncology, Case Western Reserve
University, University Hospitals Case Medical Center, 11100 Euclid Avenue,
Lerner Tower B 181, Cleveland, OH 44106, USA
Cynthia Ménard Princess Margaret Hospital, University of Toronto,
610 University Avenue, Toronto, ON, M5G 2M9, Canada e-mail: cynthia.
[email protected]
Nancy Price Mendenhall University of Florida Proton Institute, 2015 North
Jefferson Street, Jacksonville, FL 32206, USA e-mail: [email protected]fl.edu
Jeff M. Michalski Department of Radiation Oncology, Washington University
School of Medicine, Mallinckrodt Institute of Radiology, Siteman Cancer
Center, 4921, Parkview Place, St. Louis, MO 63141, USA; Department of
Radiation OncologyWashington University School of Medicine, 4921 Parkview
Place, St. Louis, MO 63110, USA
Arlan H. Mintz Department of Neurological Surgery, University of Pittsburgh
Cancer Institute, Pittsburgh, PA, USA
Contributors xiii

Gerard C. Morton Radiation Oncologist, Sunnybrook Odette Cancer Centre,

University of Toronto, 2075 Bayview Avenue, Toronto, ON, M4N 3M5,
Canada, e-mail: [email protected]
Sasa Mutic Department of Radiation Oncology Washington University School
of Medicine, Mallinckrodt Institute of Radiology, Siteman Cancer Center,
4921, Parkview Place, St. Louis, MO 63141, USA e-mail: mutic@ra-
donc.wustl.edu; [email protected].
Subir Nag Northern California Kaiser Permanente, Santa Clara, CA 95070, USA;
Stanford School of Medicine, Stanford, CA, USA
Ursula Nestle University Hospital Freiburg, Robert-Koch-Strasse 3, 79106
Freiburg im Breisgau, Germany
Roberto Orecchia Department of Radiation Oncology, European Institute of
Oncology and University of Milan, Milan, Italy
Heonjoo Park Department of Therapeutic Radiology-Radiation Oncology,
University of Minnesota, 420 Delaware St. SE, Mayo Mail Code 494,
Minneapolis, MN 55455, USA; Inha University, Inchon, Korea
Maria Pearse Radiation Oncologist, Sunnybrook Odette Cancer Centre, Uni-
versity of Toronto, 2075 Bayview Avenue, Toronto, ON, M4N 3M5, Canada;
Department of Radiation Oncology, University of Auckland Medical School,
Auckland, New Zealand
Carlos A. Perez Department of Radiation Oncology, Washington University
School of Medicine, Mallinckrodt Institute of Radiology, Siteman Cancer
Center, 4511, Forest Park Boulevard, St. Louis, MO 63141, USA; Department
of Radiation Oncology, Washington University Medical Cente, 4511, Forest
Park Boulevard, Suite 200, St. Louis, MO 63108, USA; Department of Radi-
ation Oncology, Mallinckrodt Institute of Radiology, Washington University
School of Medicine, St. Louis, MO 63110, USA
Bradley R. Pieters Department of Radiation Oncology, Academic Medical
Center/University of Amsterdam, P.O. Box 22660, Z0-214, 1100 DD Amster-
dam, The Netherlands
Philip Poortmans Department of Radiation Oncology, University of California
Davis Medical Center, Sacramento, CA 95817, USA; Department of Radiation
Oncology, Institute Verbeeten, Tilburg, The Netherlands
Floris J. Pos Department of Radiation Oncology, The Netherlands Cancer
Institute-Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX
Amsterdam, The Netherlands
James A. Purdy Department of Radiation Oncology, University of California,
Davis 4501, X Street, Suite G126, Sacramento, CA 95817, USA; Department
of Radiation Oncology, University of California Davis Medical Center, Sac-
ramento, CA 95817, USA
Keith M. Rich Department of Neurological Surgery, Washington University
School of Medicine 660 South Euclid Avenue, Campus Box 8057, St. Louis,
MO 63110, USA
xiv Contributors

Andrew E. Rosenberg Surgical Pathology, Department of Pathology, Massa-

chusetts General Hospital, Harvard Medical School, Warren 2, 30 Fruit Street,
Boston, MA 02114, USA
Marvin Rotman Department of Radiation Oncology, State University of New
York, Health Science Center at Brooklyn, 450 Clarkson Aven, Box 1211,
Brooklyn, NY 11203-2098, USA; Department of Radiation Oncology, Long
Island College Hospital, Brooklyn, NY, USA
Alan R. Schulsinger Department of Radiation Oncology, State University of
New York, Health Science Center at Brooklyn, 450 Clarkson Aven, Box 1211,
Brooklyn, NY 11203-2098, USA; Department of Radiation Oncology, Long
Island College Hospital, Brooklyn, NY, USA
Granger R. Scruggs Department of Radiation Oncology, Charles A. Sammons
Cancer Center, Baylor University Medical Center–Dallas, Texas, USA
Joseph R. Simpson Department of Radiation Oncology, Washington
University School of Medicine, 4921 Parkview Place, Campus Box 8224, St.
Louis, MO 63110, USA e-mail: [email protected]
Chang W. Song Department of Therapeutic Radiology-Radiation Oncology,
University of Minnesota, 420 Delaware St. SE, Mayo Mail Code 494, Min-
neapolis, MN 55455, USA e-mail: [email protected]
Eric A. Strom Division of Radiation Oncology, The University of Texas
M. D. Anderson Cancer Center, Houston, TX 77030, USA
Bruce Thomadsen Departments of Medical Physics, Engineering Physics,
Biomedical Engineering and Industrial and Systems Engineering, University of
Wisconsin, Madison, WI 53705, USA, e-mail: [email protected]
Robert D. Timmerman Department of Radiation Oncology, University of
Texas Southwestern Medical Center, 5801 Forest Park Road, Dallas, TX
75390-9183, USA
Dorin Todor Department of Radiation Oncology, Massey Cancer Center,
Virginia Commonwealth University, Richmond, VA 23298, USA
Erik Van Limbergen Department of Radiation Oncology, University Hospital
Leuven, Leuven, Belgium, e-mail: [email protected]
Jack Venselaar Department of Clinical Physics, Institute Verbeeten, 5000 LA,
Tilburg, The Netherlands
Dirk Verellen Department of Radiation Oncology and Biomedical Physics, UZ
Brussel, Vrije Universiteit Brussel, Brussel, Belgium
Frank Vicini Department of Radiation Oncology, Beaumont Cancer Institute,
Oakland University William Beaumont School of Medicine, Royal Oak, MI
48073, USA, e-mail: [email protected]
Rodney E. Wegner Department of Radiation Oncology University of Pitts-
burgh Cancer Institute, 5150 Centre Avenue, #545, Pittsburgh, PA 15232, USA
Contributors xv

Thomas Wiegel Department of Radiation Oncology, University Hospital, Ulm,

Germany
Ben Wilkinson Department of Radiation Oncology, Beaumont Cancer Insti-
tute, Oakland University William Beaumont School of Medicine, Royal Oak,
MI 48073, USA
Christopher G. Willett Department of Radiation Oncology, Duke University,
Durham, NC, USA
Lei Xing Department of Radiation Oncology, Stanford University, 875 Blake
Wilbur Drive Room G233, Stanford, CA 94305-5847, USA
Imran Zoberi Department of Radiation Oncology, Washington University
School of Medicine, Campus Box 8224, 4921 Parkview Place, St. Louis, MO
63110, USA
Jennifer E. Zook Department of Radiation Oncology, Indiana University
School of Medicine, 535 Barnhill Drive, RT 041, Indianapolis, IN 46202, USA
 Part I

Basic Concepts in Radiation Oncology

 Practical Time–Dose Evaluations, or How
to Stop Worrying and Learn to Love Linear
Quadratics
Jack F. Fowler

This chapter is written mainly for those who say ‘‘I don’t understand this a/b business—I can’t be
bothered with Linear Quadratic and that sort of stuff.’’ Well, it might seem boring—depending on
your personality—but it is easy, and it makes so many things in radiation therapy wonderfully and
delightfully clear. Experienced readers can turn straight to Sect. 4, about a quarter of the way
through.

Contents 5 Some of the Best-Known Schedules for Head

and Neck Tumor Radiotherapy ............................. 20
5.1 Standard Fractionation............................................... 20
1 Introduction.............................................................. 8 5.2 Hyperfractionation ..................................................... 21
5.3 Radiation Therapy Oncology Group Four-Arm
2 The Simplest Modeling ........................................... 10
Fractionation Trial (RTOG 90-03) ........................... 21
2.1 The Seven Steps to LQ Heaven: Brief Summary.... 10
5.4 Head and Neck Schedules that were Initially
3 The Seven Steps to LQ Heaven:The Details ........ 12 ‘‘Too Hot’’ in Table 2 ............................................... 22
3.1 Development of the Simple LQ Formula................. 12 5.5 Shortening the Wang 2-Fraction-a-Day Schedule
3.2 Biologically Effective Dose ...................................... 14 Using BED to Adjust Individual Doses ................... 22
3.3 Relative Effectiveness ............................................... 15 5.6 General Considerations of Head and Neck
3.4 Overall Treatment Time............................................ 16 Radiotherapy .............................................................. 24
3.5 Acute Mucosal Tolerance ......................................... 17 5.7 Appropriateness of Linear Quadratic Modeling
3.6 To Convert from BED into NTD or EQD2 Gy......... 18 in the Age of SBRT, IMRT, and IGRT? ................. 25
3.7 One Example ............................................................. 18 5.8 Do’s and Don’ts for Optimum Overall Times,
3.8 Gamma Slopes, the Standard of Precision with H&N Schedules as Examples........................... 26
of Estimates of BED or NTD ................................... 19 5.9 The Difference between the Short Value for
Mucosa of Tk = 7 Days and Longer Values
4 How to Evaluate a NewSchedule—Brief of 14–32 Days for Carcinomas is What
Summary................................................................... 19 DrivesMulti-week Fractionated Radiotherapy.......... 26
6 The Problem of Optimum Overall Time.............. 28
6.1 The Essential Condition for Any
Optimum Schedule .................................................... 28
6.2 Finding Optimum Schedules ................................... 28
6.3 Rate of Accumulation of Radiation Damage
in Normal Mucosa..................................................... 29
6.4 Faster Rate of Accumulation of Radiation Damage
in Tumors than in Normal Mucosa .......................... 29
6.5 Finding Optimum Overall Times: For Any
Radiotherapy .............................................................. 30
J. F. Fowler (&) 6.6 The Summarized Optimization Process .................. 31
Human Oncology and Medical Physics, 6.7 Constructive Lengthening and its Ability
Medical School of University of Wisconsin, to Increase Tumor-Effective Dose:
Madison, WI, USA A Counterintuitive Move?......................................... 32
e-mail: [email protected] 7 The Results: Tumor Accumulated EQD Plotted
J. F. Fowler Against Number of Fractions or Overall Time ... 32
Gray Laboratory, Northwood, London, UK 7.1 Two Fractions a Day give more Tumor Log Cell
Kill than One Fraction a Day ................................... 33
Present Address:
J. F. Fowler
150 Lambeth Road, London, SE1 7DF, UK

S. H. Levitt et al. (eds.), Technical Basis of Radiation Therapy, Medical Radiology. Radiation Oncology, 3
DOI: 10.1007/174_2011_305,  Springer-Verlag Berlin Heidelberg 2012
4 J. F. Fowler

7.2 The Effect of Assuming Faster or Slower

Abstract
Repopulating Rates.................................................... 33
7.3 The Exceptional Cases of Very This 9-section chapter begins with an elementary
Fast Repopulation ...................................................... 33 explanation of the Linear Quadratic model of
7.4 Discussion: Is One Fraction a Day Still Radiation Response, to make sure readers haven’t
to be Used? ................................................................ 34
7.5 The First Main Conclusion ....................................... 35
missed out on understanding this robust and
7.6 The Second Main Conclusion................................... 36 reliable way of comparing different schedules in
7.7 Discussion: Smaller and Smaller Fractions.............. 36 Radiation Oncology. A detailed account of its
7.8 Discussion: How Long is Really Too Long?........... 36 many applications has recently been published as
7.9 For Slightly Slower Growing Tumors,
the Radiation-only Gains for 2F/d are Notably
‘‘21 Years of BED (Biologically Effective Dose)’’
Greater than the Once-Daily Treatments.................. 37 (Fowler Br J Radiol 83:554–568, 2010). The
essential feature of this modeling is that a given
8 Discussions: How Short is Too Short?.................. 38
8.1 Discussions: Is a Week Too Short?.......................... 38 dose has very different biological effects on
8.2 Discusssion: The Increase of Therapeutic Ratio neighbouring but different tissues because of their
with More and Smaller Fractions ............................. 39 biological alpha/beta ratios and their ‘‘kick-off’’ or
8.3 Acute Mucosal Tolerance Calculations are
‘‘onset’’ times of repopulation during continuing
also Worth Doing ..................................................... 39
8.4 Incomplete Recovery (IR) as an Enhancer irradiation. In Sections 4 and 5 comparisons of
of Radiation Damage................................................. 40 actual clinical trials are presented that have shaped
8.5 Incomplete Recovery as a Loss of Effect the current and emerging schedules of treatments
in Prolonged Fractions .............................................. 44
of Head & Neck tumors, going on to SBRT
9 Conclusions ............................................................... 46 (Stereotactic Body Radiation Therapy), IMRT
References.......................................................................... 46 (intensity Modulated Radiation Therapy) and IGRT
(Image Guided Radiation Therapy). Some insights
into how the biological strategies of fractionated
radiotherapy actually deliver therapeutic advanta-
ges are introduced. Section 6 explains how
Optimum Overall Times can now be predicted,
using basially least two constraints, one for Late
Complications and the other for Acute Tolerance
Doses. This is a fairly new break-through (2008).
Section 7 goes into detail on why Overall Times
might be too short or too long, with examples from
modern schedules still being clinically trialed.
Section 8 goes further into non-standard schedules,
with updated emphasis on the Recovery Times of
various tissues and tumors, intervals between frac-
tions and extended fraction times. The chapter ends
with an explanatory table of best and next-to-best
schedules for Head and Neck radiation oncology.
The continuing need to obtain data on individual
tumor T-1=2 and repopulation is emphasized.

Abbreviations

a, alpha Intrinsic radiosensitivity. Loge

of the number of cells sterilized
non-repairably per gray of dose
of ionizing radiation
Practical Time–Dose Evaluations, or How to Stop Worrying and Learn to Love Linear Quadratics 5

b, beta Repair capacity. Loge of the num- Con-Len Constructive lengthening: when
ber of cells sterilized in a repairable adding a day (or two) followed by a
way per gray squared not-too-small fraction (or two)
a/b, alpha/ The ratio of ‘‘intrinsic radiosensi- adds to the accumulated radiation
beta ratio tivity’’ to ‘‘repair capability’’ of a damage in the tumor, rather than
specified tissue. This ratio is large allowing it to fall by tumor repop-
([8 Gy) for rapidly proliferating ulation, or minimizes any loss
tissues and most tumors. It is small CTV Clinical tumor volume. The volume
(\6 Gy) for slowly proliferating into which malignant cells are
tissues, including late normal-tissue estimated to have spread at the time
complications. This difference is of treatment, larger than the gross
vital for the success of radiother- tumor volume (GTV) by at least
apy. When beta (b) is large, both several millimeters, depending on
mis-repair and good-repair are site, stage, and location. See also
high. It is the mis-repair that causes GTV and planning treatment
the cell survival curve to bend volume (PTV)
downward Dt Time interval between fractions,
Accelerated Fractionated schedules with shorter recommended to be not less than 6 h
fractionation overall times than the conventional EBR External beam radiation
7 (or 6) weeks EGFR Epithelial growth factor receptor,
BED Biologically effective dose, pro- one of the main intracellular bio-
portional to log cell kill and there- chemical pathways controlling rate
fore more useful as a measure of of cell proliferation
biological damage than physical EQD Biologically equivalent total dose,
dose, the effects of which vary with usually in 2 Gy dose fractions. The
fraction size and dose rate. For- total dose of a schedule using, for
mally, ‘‘the radiation dose equiva- example, 2 Gy per fraction that
lent to an infinite number of gives the same log cell kill as the
infinitely small fractions or a very schedule in question. If so, should
low dose-rate’’. Corresponds to the be designated by the added digit
intrinsic radiosensitivity (a) of the ‘‘2’’ EQD2 Gy
target cells when all repairable EUD Equivalent uniform dose. A
radiation damage (b) has been construct from the DVH of a
given time to be repaired. In linear non-uniformly irradiated volume of
quadratic modeling, BED = total tissue or tumor that estimates the
dose 9 relative effectiveness (RE), surviving proportion of cells for
where RE = (1 ? d/[a/b]), with each volume element (voxel), sums
d = dose per fraction, a = intrinsic them, and calculates that dose
radiosensitivity, and b = repair which, if given as a uniform dose to
capacity of target cells the same volume, would give the
bNED Biochemically no evidence of dis- same total cell survival as the given
ease. No progressive increase of non-uniform dose. Local fraction
prostate specific antigen (PSA) size is taken into account by
level in patients treated for prostate assuming an a/b ratio for the tissue
cancer concerned
18
CI Confidence interval FLT F Fluorothymidine, a radioactive
(usually ±95%) label for freshly synthesized DNA
CLDR Continuous low dose rate to indicate actively dividing cells.