Table Of ContentINTRAOPERATIVE IRRADIATION
CURRENT CLINICAL ONCOLOGY
Maurie Markman, MD, PhD SERIEs EmToR
1. Intraoperative Irradiation: Techniques and Results, edited by L. L. GuNDERSON,
c. G. WILLETT, L. B. HARRISON, F. A. CALVO, 1999
INTRAOPERATIVE
IRRADIATION
Techniques and Results
Edited by
LEONARD L. GUNDERSON, MD, MS
Mayo Foundation and Mayo Medical School, Rochester, MN
CHRISTOPHER G. WILLET, MD
Harvard Medical School and Massachusetts General Hospital, Boston, MA
LOUIS B. HARRISON, MD
Albert Einstein College ofM edicine and Beth Israel Cancer Center, New York, NY
FELIPE A. CALVO, MD
University Hospital Gregorio Marafion, Madrid, Spain
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Library of Congress Cataloging-in-Publication Data
Intraoperative irradiation : techniques and results I edited by L. Gunderson ... [eta!.]
p. cm.-(Current clinical oncology; 1)
Includes index.
ISBN 978-1-4757-5576-3 ISBN 978-1-59259-696-6 (eBook)
DOI 10.1007/978-1-59259-696-6
1. Cancer-Intraoperative radiotherapy. I. Gunderson, Leonard L. II. Series: Current clinical oncology (Totowa,
N.J.)
[DNLM: 1. Neoplasms-radiotherapy. 2. Intraoperative Care-methods. 3. Brachytherapy-methods. 4. Radio
therapy Dosage. 5. Electrons-therapeutic use. QZ 269 I63 1999]
RD652.I567 1999
616.99'40642-dc21
DNLM/DLC 98-50919
for Library of Congress CIP
Dedications
To my wife and eternal partner Katheryn,
for her love and unfailing support of this project and throughout my career in medicine.
To my secretary Pam Speltz and to the Mayo Central Typing Pool,
for their Herculean efforts in the preparation of this textbook.
To my colleagues at MGH and Mayo,
for the opportunity to work as a team to develop and nurture IORT as a component of
treatment for the past 20 years and in caring for the physical and spiritual needs of our patients.
To the Master Healer,
for insight into the understanding of and treatment for human malignancy.
Leonard L. Gunderson
To my wife (Mary Sunday), children (Elizabeth, Julian, and Andrew), and parents (Alice and Bernanrd)
for their love and suuport,
To Herman D. Suit, physician, scientist and mentor,
whose wisdom and insight have improved the care of the cancer patient.
Christopher G. Willett
To my wife Ilene and to the rest of my family,
Robert Tatiner, Lillian and Seymour Harrison, Ellen, and Tammy Harrison,
thanks for all your love and understanding.
To my children, Barbara and Michelle, to whom I dedicate this book,
who constantly make me focus on what is truly important in life.
To the administration and my colleagues at Memorial Sloan Kettering Cancer Center,
Drs. Zvi Fuks, Warren Enker, Lowell Anderson, Murray Brennan, Alfred Cohen, Florence
Grant, and Bruce Minsky, who provided resources, encouragement, essential input and
involvement into the development of high dose rate intraoperative irradiation (HDR-IORT) at
MSKCC.
To Beth Israel Medical Center and St Luke's Roosevelt Hospital Center,
who have provided enormous resources and encouragement to continue and expand the HDR-
IORT program in our new department.
Louis B. Harrison
To my family: wife Marta and daughters Almudena, Martita, Maria and Covadonga; beloved
parents Lucia and Felipe, brother Elpidio and sister Tuti,
my first love, the school of values in which I learned to serve society
To my teachers, especially Drs. Jose Otero and Luther W. Brady,
with deep gratitude for the privilege of superb and caring education
To all of my colleagues involved in IORT procedures during the last two decades,
for their committment to excellence in cancer medicine.
Felipe A. Calvo
To the editing staff at Humana Press, especially James Geronimo and Paul Dolgert,
who have done an excellent job in collating and producing this textbook; it has been a pleasure to interact
with them in this effort.
PREFACE
Intraoperative Irradiation: Techniques and Results is a comprehensive textbook on intra-
operative irradiation (IORT) that covers topics of interest to those working in either intraop-
erative electrons (IOERT) or high-dose-rate brachytherapy (HDR-IORT), or both. Issues of
basic science and physics are covered in addition to techniques, indications, and results by
disease-site. This volume is intended for surgeons, radiation oncologists, physicists, anesthe-
siologists, medical oncologists, and all others involved either in the procedural component of
IORT (for instance, radiation therapists and operating room nurses) or in the care of patients
with cancer (for instance, internists and nurses). Most disease-site chapters have multina-
tional coauthors and both radiation oncologists and surgeons, which provides a balanced
presentation of techniques and results by disease-site and increases the international scope of
this book.
Intraoperative Irradiation: Techniques and Results is divided into five major sections. The
book begins with chapters on the general rationale for and historical perspectives ofiORT and
the radiobiology of IORT, and proceeds to a discussion of methods and techniques of treat-
ment, a presentation of normal tissue/organ tolerance to IORT, techniques and results by
disease-site, and conclusions and future possibilities.
The rationale for using IORT as a component of treatment is based on the realization that
techniques that deliver adequate doses of external beam irradiation (EBRT) often cannot
achieve dose levels adequate for local control with reasonable tolerance even with conformal
3-D techniques. As an example, for patients with locally advanced abdominal or pelvic
malignancies in whom all disease cannot be surgically removed with negative margins, ex-
ternal beam irradiation (EBRT) by itself or in conjuction with chemotherapy is usually only
palliative because EBRT doses greater than 45-50 Gy in 25-28 fractions often cannot be
delivered safely owing to the presence of dose-limiting normal structures (stomach, small
intestine, liver, kidneys). If doses of 65-70 Gy were attempted to achieve local control, severe
treatment-related complications might result that could require hospitalization and operative
intervention. A preferred treatment approach is to administer tolerable EBRT doses of 45-
50 Gy preoperatively (1.8-2 Gy fractions), often in conjunction with concomitant chemo-
therapy, and deliver the remaining irradiation as an IORT supplement at the time of surgical
exploration and maximal resection. The IORT component of treatment then becomes the
optimal conformal irradiation technique, since dose-limiting normal organs such as stomach
and small intestine can be surgically displaced while IORT is delivered to the high-risk region
of narrow surgical margin or proven residual disease. The high-dose IORT volume is smaller
than what could be delivered with any EBRT technique, as is given with appositional IOERT
or HDR-IORT applicators.
Methods and techniques of IORT treatment are discussed in Section II in a group of five
chapters. Surgical and irradiation philosophies and techniques (EBRTIIORT) are discussed
as they apply to IORT in general, and physics aspects of IORT are presented with regard to
both IOERT and HDR-IORT. The physics chapters contain practical information concerning
issues of dosimetry and applicator design as well as more esoteric factors of facility construc-
tion and shielding (for those contemplating a new or retrofitted facility) and specialized
equipment (mobile IOERT machine-Mobetron and Novac-7). The technique chapters in-
clude discussions of appropriate interactions between surgeon, radiation oncologist, and an-
esthesiologist; applicator selection for both IOERT and HDR-IORT; energy and dose of
IOERT and HDR-IORT dose based on amount of residual disease after maximal resection and
Vll
viii Preface
other factors of interest to both the surgeon and radiation oncologist. Figures are used amply
to discuss some of the above issues. Chapter 7 is a unique, balanced discussion of the
comparative advantages and disadvantages of IOERT, HDR-IORT, and perioperative
brachytherapy with a senior author whose institution utilizes all three techniques and coau-
thors being the coeditors of the textbook who have vast experience with I OERT or HD R-I ORT
(+ 1- peri operative brachytherapy). The conclusion of the chapter is that large institutions
would best serve their patients by having at least two of the three options available in an
operating room setting.
Section III contains three chapters that discuss normal tissue tolerance to IORT. Single
institution results from NCI and Colorado State University (CSU) present animal tolerance
data in a vast array of organs or structures (separate chapters from each institution that also
include data from other animal series and some human data as well). The NCI animal data are
based totally on the use of single-dose IORT, while the CSU data include invaluable informa-
tion concerning relative tolerance with EBRT alone (60, 70, or 80 Gy delivered in 30 fractions
over 6 wk) vs IORT alone (17.5-55 Gy) vs EBRT plus IORT (EBRT of 50 Gy/ 25 fractions;
IORT of 10-47.5 Gy). The remaining chapter contains both animal and human data on the
tolerance of peripheral nerve, which is the dose-limiting structure for IORT. These three
chapters are essential reading for any individuals who are contemplating a program involving
IORT, as the implications of tolerance are far reaching for the patients who will receive IORT
as well as for the physicians involved in the delivery of IORT.
The largest section contains the disease-site chapters on every disease-site in which poten-
tial merit for IORT has been demonstrated in one or more institutions or countries. Disease-
specific treatment factors are presented by the radiation oncology and surgeon coauthors.
Results with standard non-IORT treatment are presented for most chapters as a basis for
comparing results when IORT is used as a component of treatment. Treatment outcomes data
include disease control (local and distant) survival (disease-free and overall) and treatment
tolerance. Seven ofthe 18 disease-site chapters relate to GI cancers (three chapters on colo-
rectal cancer and separate chapters on gastric, pancreatic, biliary tract, and liver); five ofthe
seven chapters contain data with IOERT techniques and four of the seven contain data on
either HDR-IORT or perioperative brachytherapy. The remaining 11 disease-site chapters
include four on sarcomas (separate chapters on either IOERT or HDR-IORT for retroperito-
neal/pelvic sarcoma, IOERT for bone sarcomas, IOERT or perioperative brachytherapy for
extremity sarcomas) and single chapters on gynecologic, genitourinary, lung, head/neck,
pediatric, CNS, and breast malignancies.
The closing section is a chapter on conclusions and future possibilities written by the four
coeditors. The conclusion is that experience has shown that variable combinations of EBRT,
IORT (IOERT or HDR-IORT), and maximal surgical resection are feasible and practical in
settings where close interdisciplinary cooperation exists. Furthermore, these aggressive ap-
proaches that include IORT appear to improve significantly local control, if not survival, in
a large number of disease sites when compared to results achieved with standard treatment
approaches. However, when gross residual or unresectable disease remains in spite of at-
tempts at a gross total resection or when patients have received prior EBRT in an adjuvant
setting, the ability to achieve central or local control is lessened, thus creating the need for
prospective trials that address the addition of radiation dose modifiers (sensitizers, hyperther-
mia, etc.) during both EBRT and IORT. The patients with locally advanced disease who are
ideal candidates for the locally aggressive approaches often have moderate to high systemic
risks as well. Prospective trials are therefore indicated to address the addition of systemic
Preface ix
therapy to optimal locally aggressive combined treatment. Finally, the issue of peripheral
nerve tolerance could be addressed by prospective phase II and III studies that evaluate the
issue of improving nerve tolerance with the addition of the radioprotector Amifostine. This
chapter also includes a discussion on improvements in technology that make IORT more
feasible in a larger number of institutions and will facilitate the conduct of the previously
mentioned trials (HDR-brachytherapy equipment that can be used in either an outpatient or
operating room setting; mobile IOERT equipment including Mobetron and Novac-7).
The editors are indebted to the many international experts who participated in this project
as either the primary author or co-authors. As a result of their superb efforts, Intraoperative
Irradiation: Techniques and Results should be an appropriate resource and reference book
for many years to come. The myriad of prospective trials that are indicated to test issues
of optimized local control, distant control and tolerance will be best carried out in the setting
of a multi-institutional international cooperative group that is reflected in the authorship of
this volume.
Leonard L. Gunderson
Christopher G. Willett
Louis B. Harrison
Felipe A. Calvo
CONTENTS
Preface .................................................................................................................................. vii
Contributors .......................................................................................................................... xv
pART I. GENERAL RATIONALE AND HISTORICAL PERSPECTIVE
1 General Rationale and Historical Perspective of Intraoperative Irradiation .............. 1
Leonard L. Gunderson, Felipe A. Calvo, Christopher G. Willett,
Louis B. Harrison, and Manuel Santos
2 Biology of Large Dose per Fraction Radiation Therapy ............................................ 25
Paul Okunieff, Srinath Sundararaman, and Yuhchyaw Chen
PART II. METHODS AND TECHNIQUES OF TREATMENT
3 Physical Aspects of Intraoperative Electron-Beam Irradiation ................................. 47
Edwin C. McCullough and Peter J. Biggs
4 IOERT Treatment Factors: Technique, Equipment .................................................... 65
Christopher G. Willett, Leonard L. Gunderson, Paul M. Busse,
David Nagorney, Joel E. Tepper, and Felipe A. Calvo
5 Physics of Intraoperative High-Dose-Rate Brachytherapy ........................................ 87
Lowell L. Anderson, Patrick J. Harrington, and Jean St. Germain
6 High-Dose-Rate Intraoperative Irradiation (HDR-IORT): Technical Factors ........ 105
Louis B. Harrison, Alfred M. Cohen, and Warren E. Enker
7 Intraoperative Irradiation with Electron-Beam or High-Dose-Rate Brachytherapy:
Methodological Comparisons ............................................................................... 111
Subir Nag, Leonard L. Gunderson, Christopher G. Willett,
Louis B. Harrison, and Felipe A. Calvo
PART III. NoRMAL TissuE ToLERANCE-IORT
8 Normal Tissue Tolerance to Intraoperative Irradiation:
The National Cancer Institute Experimental Studies ........................................... 131
William F. Sindelar, Peter A. S. Johnstone, Harald J. Hoekstra,
and Timothy J. Kinsella
9 Studies at Colorado State University of Normal Tissue Tolerance of Beagles
to IOERT, EBRT, or a Combination ..................................................................... 147
Edward L. Gillette, Sharon M. Gillette, and Barbara E. Powers
10 Peripheral Nerve Tolerance: Experimental and Clinical ......................................... 165
Edward Gillette, Barbara E. Powers, Sharon M. Gillette,
Leonard L. Gunderson, and Christopher G. Willett
pART IV. RESULTS OF IORT WITH OR WITHOUT EBRT BY DISEASE SITE
11 Gastric IORT With or Without EBRT ...................................................................... 175
Rafael Martinez-Monge, Jean P. Gerard, H. J. Kramling,
F. Guillemin, and Felipe A. Calvo
xi
