Table Of ContentRecent Results 103
in Cancer Research
Founding Editor
P. Rentchnick, Geneva
Managing Editors
Ch. Herfarth, Heidelberg. H. J. Senn, St. Gallen
Associate Editors
M. Baum, London· V. Diehl, Koln
C. von Essen, Villigen . E. Grundmann, Munster
W. Hitzig, Zurich . M. F. Rajewsky, Essen
Recent Results in Cancer Research
Volume 95: Spheroids in Cancer Research
Edited by H. Acker, J. Carlsson, R. Durand, R. M. Sutherland
1984.83 figures, 12 tables. IX, 183. ISBN 3-540-13691-6
Volume 96: Adjuvant Chemotherapy of Breast Cancer
Edited by H.-J. Senn
1984.98 figures, 91 tables. X, 243. ISBN 3-540-13738-6
Volume 97: Small Cell Lung Cancer
Edited by S. Seeber
1985. 44 figures, 47 tables. VII, 166. ISBN 3-540-13798-X
Volume 98: Perioperative Chemotherapy
Edited by U. Metzger, F. Largiader, H.-J. Senn
1985.48 figures, 45 tables. XII, 157. ISBN 3-540-15124-9
Volume 99: Peptide Hormones in Lung Cancer
Edited by K. Havemann, G. Sorenson, C. Gropp
1985. 100 figures, 63 tables. XII, 248. ISBN 3-540-15504-X
Volume 100:
Therapeutic Strategies in Primary and Metastatic Liver Cancer
Edited by Ch. Herfarth, P. Schlag, P. Hohenberger
1986.163 figures, 104 tables. ISBN 3-540-16011-6
Volume 101:
Locoregional High-Frequency Hyperthermia and Temperature
Measurement
Edited by G. Bruggmoser, W. Hinkelbein, R. Engelhardt,
M. Wannenmacher
1986.96 figures, 8 tables. IX, 143. ISBN 3-540-15501-5
Volume 102: Epidemiology of Malignant Melanoma
Edited by R. P. Gallagher
1986. 15 figures, 70 tables, IX, 169. ISBN 3-540-16020-5
Preoperative (Ne oadjuvant)
Chemotherapy
Edited by
J. Ragaz, P. R. Band, and J. H. Goldie
With 58 Figures and 49 Tables
Springer-Verlag
Berlin Heidelberg New York Tokyo
Joseph Ragaz, M. D.
Pierre R. Band, M. D.
James H.Goldie, M.D.
Cancer Control Agency of British Columbia
600 West 10th Avenue
Vancouver, B. C. V5Z 4E6, Canada
ISBN-13: 978-3-642-82673-3 e-ISBN-13: 978-3-642-82671-9
001: 10.1007/978-3-642-82671-9
Library of Congress Cataloging-in-Publication Data. Main entry under title: Preoperative
(neoadjuvant) chemotherapy. (Recent results in cancer research; 103) Includes
bibliographies and index. 1. Cancer-Adjuvant treatment. 2. Preoperative care. I. Ragaz, J.
(Joseph), 1945- . II. Band, P. R. (Pierre R.), 1935- . III. Goldie, James H. IV. Series.
[DNLM: 1. Adjuvants, Immunologic-therapeutic use. 2. Adjuvants, Pharmaceutic
therapeutic use. 3. Neoplasms-drug therapy. 4. Preoperative Care.
WI RE106P v.l03/QZ 267 P927] RC261.R35 vol. 103 616.99'4s
[616.99'4061] 85-30312 [RC27I.A35]
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© Springer-Verlag Berlin Heidelberg 1986
Softcover reprint of the hardcover I st edition 1986
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Preface
Despite recent advances in adjuvant therapies of cancer, the regi
mens of postoperative adjuvant chemotherapy treatment which are
presently available fail to cure the majority of cancer patients. Pre
operative (neoadjuvant) chemotherapy represents a new approach
in drug scheduling, based on sound theoretical, pharmacokinetic,
and experimental principles.
The preoperative timing of chemotherapy before definitive sur
gery is not a minor change in the therapy of cancer. To be successful,
large numbers of practitioners and their patients must participate.
Substantial alterations of many aspects of the present management
of cancer will have to follow. Therefore, before such therapy can be
fully and routinely implemented, results of the novel treatment and
its rationale have to be carefully evaluated.
In preoperative treatment, other features will likely gain impor
tance. For the first time, clinicians have a chance to follow the in
vivo response of the tumor exposed to preoperative chemotherapy.
The subsequent histological assessment of the tumor sample may
likely become an important prognostic guide, permitting more re
fined individual approaches to the planning of postoperative adju
vant treatment. The value of such a treatment strategy can already
be appreciated in the clinical setting, as seen from the therapy of
osteosarcoma. Furthermore, preoperative chemotherapy might
render previously inoperable tumors operable and hence resectable
with a curative intention. The preoperative reduction of tumor bulk
may also effectively decrease the need for more radical operations,
permitting a more uniform adoption of conservative surgery. Al
though the most important departure from conventional adjuvant
treatment, the preoperative timing of chemotherapy is, therefore,
not the only element of the neoadjuvant approach.
Our Vancouver symposium took place in March 1985. In organiz
ing the convention we were greatly helped by a generous grant of
Lederle Canada and their international branch, as well as by the
competent assistance of Betty Fata and Lisa Lockerby from the con
ference organizing company Venue West. Invited speakers summa
rized the current preclinical and clinical aspects of neoadjuvant
chemotherapy. The material presented represents an update and a
comprehensive review of the key issues of the neoadjuvant therapy
of cancer.
VI Preface
We hope that the present efforts and research on preoperative
chemotherapy, as reflected in this volume, represent only a begin
ning rather than the end of what looks like a very promising ap
proach towards the therapy of cancer.
Vancouver, Canada
December 1985 J.Ragaz
P. R. Band
J.H. Goldie
Contents
E. Frei III, D. Miller, J. R. Clark, B. G. Fallon, and T. J. Ervin
Clinical and Scientific Considerations in Preoperative
(Neoadjuvant) Chemotherapy ........... . . 1
H. E. Skipper
Experimental Adjuvant Chemotherapy: An Overview 6
J. H. Goldie and A. J. Coldman
Theoretical Considerations Regarding the Early Use of
Adjuvant Chemotherapy . . . . . . . . . . . . . . . . . 30
L. M. van Pullen
Experimental Preoperative Chemotherapy ........... 36
B. T.Hill
Implications of Certain Cell Kinetic and Biological Parameters
for Preoperative Chemotherapy. . . . . . . . . . . . . . . . .. 41
B.Fisher
Adjuvant Therapy for Breast Cancer:
A Brief Overview of the NSABP Experience and
Some Thoughts on Neoadjuvant Chemotherapy . . ... 54
A. J. Coldman and J. H. Goldie
Factors Mfecting the Development of Permanent Drug
Resistance and Its Impact upon Neoadjuvant Chemotherapy 69
R. M. Baird and P'A.Rebbeck
Impact of Preoperative Chemotherapy for the Surgeon . . .. 79
J.Ragaz
Preoperative (Neoadjuvant) Chemotherapy for Breast Cancer:
Outline of the British Columbia Trial. . . . . . . . . . . . . .. 85
R. Nissen-Meyer, H. Host, K. Kjellgren, B. Mansson,
and T.Norin
Perioperative Adjuvant Chemotherapy of Breast Cancer:
The Scandinavian Experience. . . . . . . . . . . . . . .. .. 95
A. Goldhirsch and R. Gelber
Peri operative and Conventionally Timed Chemotherapy in
Operable Breast Cancer: The Ludwig Breast Cancer Study V . 103
VIII Contents
C. I. Jacquillat, M. Weil, G.Auc/erc, M. Sellami, M. F.Auc/erc,
D. Khayat, and F. Baillet
Neoadjuvant Chemotherapy in the Conservative Management
of Breast Cancer: Study of 143 Patients .............. 113
J. Clavier, L. Israel, G. Nouvet, Y. Raut, J.-J. Gres, J.-F. Morere,
C. Zabbe, G. Lerebours-Pigeonniere, and J.-L. Breau
Preliminary Results of Preoperative Chemotherapy with a
Combination of Platinum-Bleomycin Administered in 5-Day
Cycles in Carcinoma of the Bronchus ............ . 120
L.A. Price and B. T. Hill
Impact of Primary Site of Stage III and IV Squamous Cell
Carcinomas of the Head and Neck on 7-Year Survival Figures
Following Initial Non-Cisplatin-Containing Combination
Chemotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . 124
A. N. Papaioannou, A. P. Polychronis, J.A. Kozonis, J. Nomicos,
M. Tsamouri, G.A. Plataniotis, and J. K. Papageorgiou
Chemotherapy with or Without Anticoagulation as Initial
Management of Patients with Operable Colorectal Cancer:
A Prospective Study with at Least 5Years Follow-up ...... 135
A. N. Papaioannou, J.A. Kozonis, A. P. Polychronis, J. Nomicos,
G.A. Plataniotis, and J. K. Papageorgiou
Preoperative Chemotherapy for Gastric Cancer:
A Prospective Study with at Least 1 Year Follow-up. . ... 142
G.Rosen
Neoadjuvant Chemotherapy for Osteogenic Sarcoma:
A Model for the Treatment of Other Highly Malignant
Neoplasms . . . . . . . . . . . . . . . . . . . . . . . . . . 148
J. M. Goldie, P. Band, and J. Ragaz
Summary of Preoperative (Neoadjuvant) Chemotherapy. . 158
Subject Index. . . . . . . . . . . . . . . . . . . . . . . .. . 160
List of Contributors *
Aucierc, G. 1131 Lerebours-Pigeonniere, G. 120
Aucierc, M. F. 113 Mansson, B. 95
Baillet, F. 113 Miller, D. 1
Baird, R. M. 79 Morere, J.-F. 120
Band,P.158 Nissen-Meyer, R. 95
Breau, J.-L. 120 Nomicos, J. 135, 142
Clark, J. R. 1 Norin, T. 95
Coldman, A.J. 30, 69 Nouvet, G. 120
Clavier, J. 120 Papageorgiou, J. K. 135, 142
Ervin, T.J. 1 Papaioannou, A. N. 135, 142
Fallon, B. G. 1 Plataniotis, G.A. 135, 142
Fisher, B. 54 Polychronis, A. P. 135, 142
Frei III, E. 1 Price, L. A. 124
Gelber, R. 103 Putten van, L. M. 36
Goldie, J. H. 30, 69, 158 Ragaz, J. 85, 158
Goldhirsch, A. 103 Raut, Y.120
Gres, J.-J. 120 Rebbeck, P. A. 79
Hill, B. T. 41, 124 Rosen, G. 148
Host, H. 95 Sellami, M. 113
Israel, L. 120 Skipper, H. E. 6
c.1.
J acquillat, 113 Tsamouri, M. 135
Khayat, D. 113 Weil, M.113
Kjellgren, K. 95 Zabbe, C. 120
Kozonis, J.A. 135, 142
* The adress of the principal author is given on the first page of each contri
bution
1 Page on which contribution begins
Clinical and Scientific Considerations
in Preoperative (Neoadjuvant) Chemotherapy
E. Frei III, D. Miller, J. R. Clark, B. G. Fallon, and T. J. Ervin
Dana· Farber Cancer Institute, 44 Binney Street, Boston, MA 02115, USA
Introduction
Thirty years ago, chemotherapy had little to offer patients with solid tumors and in gener
al patients were treated after failure of surgery or radiotherapy when advanced overt
metastatic disease was already present. As progress was made in the chemotherapy of the
childhood solid tumors, and of certain adult tumors, such as metastatic breast cancer, the
investigation of chemotherapy in the adjuvant situation developed. This was stimulated by
the fact that, for example, patients with stage II breast cancer or osteogenic sarcoma are at
high risk of having micro metastatic dissemination at the time of diagnosis, so that poten
tially definitive treatment must include not only control of the primary with surgery andl
or radiotherapy (SIR), but also systemic chemotherapy (C), the latter to control dissemi
nated micrometastatic disease. The experimental basis for this was the observation that
chemotherapy for in vivo transplanted tumors was capable of cytoeradication (cure) in in
verse relationship to the tumor burden. Thus chemotherapy which produced only partial
regression of advanced tumor was frequently curative when applied to the same tumor in
microscopic form (Goldin et al. 1956). This was also demonstrated in experimental in vivo
systems, wherein the primary in the extremity was controlled by amputation, following
which the cure rate could be increased in many circumstances by chemotherapy ad
dressed to micrometastatic disease (Skipper 1978).
A more recent evolution of multidisciplinary treatment strategy has been the use of C
initially, followed by SIR, in patients with solid tumors. The purpose of this approach is
(1) to improve control of the primary by stage reduction andlor (2) to improve control of
micrometastatic disease. Examples include head and neck cancer, where the major prob
lem is control of the primary; breast cancer and osteogenic sarcoma, where the major
problem is control of micro metastatic disease; and lung cancer, where control of both 10-
coregional and disseminated micrometastatic disease is a major problem.
I have chosen the term "neoadjuvant chemotherapy" for this strategy (Frei 1982). It per
petuates the term "adjuvant" which, though it was an unfortunate choice, is thoroughly
entrenched. Also, it is a hybrid of generic terms. I prefer "neoadjuvant," however, because
it is unambiguous, in contrast to other terms, such as "preoperative chemotherapy," which
leaves out the important discipline of radiotherapy, and "induction chemotherapy,"
which has an old and well-defined meaning, in the context of the leukemias. Neoadjuvant
chemotherapy (NA-C) is not a novel strategy in a sense, since it was employed successful
ly 15-20years ago in the multidisciplinary treatment of childhood solid tumors, and
studies have been performed in the past of some adult solid tumors. However, it is new as
a strategy for adult solid tumors, in the sense that progress in chemotherapy has made it
an idea whose time has come.
Recent Results in Cancer Research. Vol 103
© Springer-Verlag Berlin· Heidelberg 1986
