Clinical Trials in ‘Early’ Breast Cancer: Methodological and Clinical Aspects of Treatment Comparisons Proceedings of a Symposium, Heidelberg, Germany, 4th to 8th December, 1978

288 Pages·1979·7.808 MB·English

by  Hans Scheurlen (auth.), H. R. Scheurlen, G. Weckesser, I. Armbruster (eds.)

Lecture Notes in
Medical Informatics
Edited by D. A. B. Lindberg and P. L. Reichertz
4
Clinical Trials
in 'Early' Breast Cancer
Methodological and Clinical Aspects
of Treatment Comparisons
Proceedings of a Symposium, Heidelberg, Germany,
4th to 8th December, 1978
Edited by
H. R. Scheurlen, G. Weckesser and I. Armbruster
Springer-Verlag
Berlin Heidelberg New York 1979
Editorial Board
J. Anderson, J. H. van Bemmel, M. F. Collen, S. Kaihara, A Levy,
D. A B. Lindberg (Managing Editor), H. Peterson, A Pratt,
P. L. Reichertz (Managing Editor), W. Spencer, K. Oberia, C. Vall bona
Editors of this Volume
H. R. Scheurlen
G. Weckesser
I. Armbruster
Institut fi.ir Medizinische
Ookumentation, Statistik
und Oatenverarbeitung
der Universitat
1m Neuenheimer Feld 325
0-6900 Heidelberg 1
ISBN-13:978-3-540-09530-9 e-ISBN-13:978-3-642-93118-5
001: 10.1007/978-3-642-93118-5
Library of Congress Cataloging in Publication Data
Main entry under title:
Clinical trials in 'early' breast cancer.
(Lecture notes in medical informatics; v. 4)
Bibliography: p.
Includes index.
1. Breast--Cancer--Prognosis--Statistical methods--Congresses.
I. Scheurlen, Hans. II. Weckesser, G., 1948-III. Armbruster, Inge, 1953-IV. Series.
RC280.BBC59 616.9'94'49 79-19183
ISBN-13:978-3-540-09530-9
This work is subject to copyright. All rights are reserved, whether the whole or part of the
material is concerned, specifically those of translation, reprinting, re-use of illustrations,
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© by Springer-Verlag Berlin Heidelberg 1979
2141/3140-543210
Pre f ace
In the present situation of clinical trials it seems a worthwhile task
to bring clinicians and statisticians together to talk about common
problems. When, in summer 1978, the Deutsche Forschungsgemeinschaft
made available the resources for a scientific meeting we did not hesi
tate to submit such a cooperative project.
We are grateful to the members of the Sonderforschungsbereich 123
'Stochastische Mathematische Modelle' for giving precedence to that
project.
Above all we thank Prof. Dr. H. Immich who gave us support with word
and deed from the very beginning.
Our thanks are also due to Sarah Nelson who helped us by looking
through the comments as well as preparing the papers for publication.
Finally we would like to thank Mrs. Heidrun Wunsch for her expert
re-typing most of the papers.
Following the idea of our symposium much attention is given in this
book to discussions. Thus the reader may form a picture of whether
such a meeting deserves to be repeated.
H.R. Scheurlen
G. Weckes,s,er
I. Armbruster
CONTENTS
In troduction .••..•.•..•............•....•.....•.........•....
H.R. Scheurlen
Part 1. General Aspects
Prognostic Factors and Nosological Criteria of Breast Cancer
from the Pathologist's Point of View....................... 7
R. Baessler
Growth Rate of Tumours and Natural Life Expectancy........... 20
D.v.Fournier
The Reporting of Non-significant Results in Clinical Trials.. 28
J.L. Haybittle
Notes on Clinical Trial Methodology........... ............... 40
R. Peto
Part 2. Design and Performance of Clinical Trials
The Cardiff Mastectomy Trial .•.....•••••..••...•••••......... 45
M. Maureen Roberts
Experiences from a Multicentric Trial of Adjuvant Chemotherapy 61
R. Nissen-Meyer
Thirty Years Experience with Breast Cancer Clinical Trials at
the Christie Hospital in Manchester - Clinical Aspects ....• 71
G.G. Ribeiro
Thirty Years Experience of Breast Cancer Trials in Manchester -
Statistical Aspects ...••......•.......•.•.••........•...•.. 75
M.K. Palmer
The King's/Cambridge Trial .•.•.•.••..••••.•.........••...••.. 87
M. Baum
Operable Breast Cancer with Positive Axillary Nodes:
The Experience of the Milan Cancer Institute •.••........•.. 104
Pinuccia Valagussa, A. Rossi, G. Bonadonna
Part 3. Treatment Departures
Problems in Withdrawal of Patients in a Randomized Study,
when Treatment in One of the Groups Cannot be Carried Out 112
S. Kaae, H. Johansen
Treatment Departure and Survival Analysis in a Randomized
Trial on the Value of Pre- and Postoperative Radiotherapy
in Breast Cancer ..•.•.......•.•..••••.•••••.•...••..••.•... 117
A. Wallgren, Britta Mattsson, L. Karnstrom
Part 4. Stochastic Models
Stochastic Models in Clinical Trials .••..•.•.•.•...•.•...•... 123
S.W. Lagakos
VI
Part 5. Regression Models
Aspects of the Cox Model in the Analysis of Survival Data .... 143
R. Kay
Time Dependend Covariates ..........•...•.•...•.•......••..... 159
J.D. Kalbfleisch
A Large Sample Study of the Estimate for the Survival
Distribution in Cox's Regression Model .••.•...•.•.•...•.•.• 172
A.A. Tsiatis
Part 6. Competing Risks
Comparing Treatments, Adjusting for Competing Risks ••....•..• 181
M.L. Moeschberger
Why the Present Approach to Competing Risks Should be
Abandoned •..••..••.•••••....••.••••...•••••••••.•••.•.•.••. 1 93
A.A. Tsiatis
Competing Risk Models in Early Breast Cancer Trials ••...••.•. 202
R.L. Prentice
Part 7. Log Rank Test
Some Extensions of the Log Rank Test ••••.•••..••••••.......•• 213
John Crowley
Discussion ••.•••.••••.•..••••••..••••••••.•••••••••.•.•.•.•.•... 224
Sarah Nelson
Appendix
Controlled Illness Processes with Incomplete Information -
A Re-examination of the Basic Hypothesis in Constructing
Stochastic Models .••..••.••.•••••.••.•••••••••••.•••.•••••• 243
P. Tautu
List of Participants 281
I n t rod u c t ion
Hans Scheurlen
Institut fur Medizinische Dokumentation,
Statistik und Datenverarbeitung
Universitat Heidelberg
Thirty years ago Paterson and Russell initiated the first controlled
clinical trial in the field of treatment for breast cancer. At almost
the same time Boag published his paper on "maximum likelihood estimates
of the portion of patients cured by cancer therapy". Since then, both
clinicians and statisticians have been increasingly devoting themselves
to the problem of how to express the efficiency of treatments in terms
of the patients' chance of survival. The incorporation of regression
like arguments into life table analysis, as proposed by D.R. Cox in
1972, seems to apply to a vast variety of real situations and has led
to a remarkable number of papers from the statisticians.
However, we also have reason to view with concern what is going on. Do
the new concepts inspire the clinical experimenters to put their problem
more precisely? Do controlled trials have any influence on the medical
practice of treating patients at all?
We have addressed these questions in a more detailed form to expert
clinicians and statisticians (see the appendix of the Discussion) ,
inviting them to discuss these questions on the occasion of our
symposium. The limitation of the general theme to a particular stage
of a particular disease served two purposes: the selection of the
clinicians and the stimulation of the participants to reach some feasible
results.
To give a provisional answer I feel that the clinicians and the statisti
cians have become progressively estranged, this being the other side
of the recent Fleasing productivity of the statisticians. If that is
the case I think it is unpleasant. It may be useful in this context to
consider the medical history (I) and the present state (II) of our
problem.
I
In the nineteenth century, during the period of antisepsis, French and
German surgeons had a violent controversy about operations in the case
of breast cancer. Verneuille, a spokesman of the French, objected to
2
operating on patients unless the disease seemed to be in a very early
stage. In the vast majority of cases, however, he considered breast
cancer to be far advanced and thus any operation to be useless or even
harmful, since it frequently was seen to be followed by a dramatic turn
to the worse. Billroth from Vienna, the leader of the German surgeons,
wanted to give operations in all cases. He maintained that a considerable
number of patients was spared in this way and that some patients even
lived for many years without recurrence. His failures are nevertheless
indisputable, as one can see from the case reports, published in 1878
by A. von Winiwarter.
William Stewart Halsted had the opportunity to watch Billroth working
when he visited Vienna in 1879. From that he concluded that the technique
used in Vienna was without any sound foundation, leaving parts of the
tumour mass unremoved in most cases. As Haagensen pOinted out, Billrdb
in fact was "treating breast cancer with what we would today describe
a simple mastectomy and in some patients also with limited axillary
dissection". Stressing the locally advanced but non-systemic nature of
the disease, Halsted consequently developed his radical technique of
mastectomy when he returned to New York.
The short-term results of the radical mastectomy looked quite pnmUssing.
Some ten years later, however, surgeons had to confess that despite a
marked decrease in local recurrence rates the majority of patients died
with metastatic disease anyway. In 1902 Pusey, Beck and Turner reported
on the radiosensitivity of inoperable breast tumours and descr~ some
successful cures using radiotherapy. Some doctors therefore hoped to
improve their results by giving radiotherapy in addition to radical
mastectomy. In Germany some hospitals began to routinely use postoperative
radiotherapy in 191 2. As a result a further decrease of local recurrences
was found by those using relatively high radiation doses. The question
whether adjuvant radiotherapy has an influence on the survival time as
well caused a dispute between surgeons and radiologists. Papers con
cerning this controversy caused the literature to swell like an avalanche.
During the thirties, however, critical contemporaries already had their
doubts about the validity of the "Halsted doctrine". If the prevention
of local recurrences is not related to some substantial improvements
of the patients' chance of survival then the disease cannot be limited
at the time of operation so frequently, as was assumed previously.
McWhirter considered the surgical manipulation itself a possible cause
of dissemination. He proposed the hypothesis, that the frequency of
3
such an event is related to the extension of a manipulation anyway. In
1941 more than forty surgeons from Southeast Scotland decided to replace
the classic Halsted procedure by a combination of simple mastectomy and
postoperative irradiation. As far as possible all women with breast
cancer from that region were included. By a historical comparison
McWhirter, in 1949, drew the conclusion that the so-called McWhirter
method is superior to radical mastectomy (with or without adjuvant
radiotherapy).
Using historical comparisons is a dangerous procedure because it is
impossible to distinguish between a real difference in treatments and
(what Berkson called) a general "time trend" towards a more favourable
survivorship of primary treated patients. As Berkson has pOinted out
this "time trend" does not vanish even if the samples are stratified
for comparison by aid of relevant prognostic factors. Moreover, the
question whether unrandomized series are comparable, whatever their
nature, remains "the devil's own question" being the root of all con
fusion within the medical literature up to now.
Meanwhile the physicians have perceived that randomization of patients
is a necessary prerequisite for treatment comparisons. Since the onset
of the Manchester trial thirty years ago a lot of clinical trials have
been carried out and analysed (whether intermediately or finally).
Physicians are now in a position to judge the situation more cautiously.
Unfortunately they do not yet agree, even on those pOints which have
been re-examined repeatedly in the past. Recently clinical trials have
been aparently focussed mainly on two problems:
(i) Which is most effective, a conservative or radical operation?
(ii) Is there any improvement of the results of local therapy when
adjuvant systemic treatment was added?
II
The motives for planning an experiment are greatly different, comprising
conflicts with traditional philosophies (such as the "Halsted doct rine")
as well as simple chance discoveries. However, it seems impossible to
find any experiment to be derived from others in a more systematic
manner. Whenever the clinician is consulted by a patient he will be
faced with a complex variety of treatment policies which cannot be kept
on a simple conservative-radical scale. However, a comparison of more
than two or three treatments at once is very rare amongst the reported
trials.
4
Are there any common conclusions therefore to be drawn from the results
of several experiments when the treatments of one experiment are,partly
or completely, different from those of another one, or when neither the
criteria for acceptability of patients nor the criteria for stratification
are comparable? What conditions are necessary for experimental strate
gies to be comparable enough to make common conclusions?
Instead of giving an answer I would like to stress another point which
is connected with the question of compatibility and with some special
features of clinical experimentation as well. When devising and per
forming clinical trials we must be aware of the fact that patients on
study are entitled not only to the best possible therapy but also to
the freedom of choice whether to continue or to refuse the treatment
ass~ned to them by random allocation. If this is true, protocol devia
tions will be inevitable. The subsample comprising those deviants is
by no means randomly drawn from the population of the accepted patients.
Its size and bias will have an influence on the resultof the experiment.
Size and bias themselves are related to some experimental conditions
such as
(i) the patients' "informed consent",
(ii) the mental and somatic stress due to the treatments,
(iii) the time of randomization.
To make the third point clear let us consider two experiments with
postoperative irradiation being one of the treatments and let the time
of randomization be the only difference between the two experiments,
this being soon after the mastectomy (at R,) and right before the begin
ning of irradiation (at R2) respectively (see the following figure
with M, R R2 the time of mastectomy and randomization respectively
"
and I the period of irradiation).
Experiment 1
t
M
Experiment 2
t
Routinely used irradiation is impossible when patients have a relapse
between R, and R2. Patients possibly refuse irradiation when they are
prior to R2 either in an excellent condition or a very poor condition
from causes other than cancer. In experiment 1 all these patients are
5
protocol deviants causing bias when excluded from evaluation and leading
to ill-defined treatments when put on test. In experiment 2 handling
this sort of patients is no problem at all. However, in experiment 2
the target population is not quite the same as in experiment 1.
The clinician is finally interested in the "significance" of the result
of his experiment. He is now faced with questions concerning the choice
of time for testing and the choice of test procedure to be applied,
giving rise to some arbitrariness. For example let us assume that a
decision is to be taken between a conservative policy and a radical one.
Let us further assume that the portion of patients cured as well as the
portion injured is raised by the radical treatment. As a consequence
some patients will die either very early or very late after the radical
treatment as compared with the conservative policy. Possibly the result
of a trial might be "not significant" when using a plausible procedure
such as the generalized Wilcoxon test but "significant" when using the
logrank test which looks just as plausible. What is the meaning of
"significant"?
Clearly the answer depends on what the clinician really wants to find
out, i.e. on the statement of his problem and the formulation of his
hypotheses. Some subjects of those statements are: the probability that
a patient survives x years, the life expectancy, the median survival
time, the portion of patients cured, some net or partial crude proba
bilities, some parameters of a particular distribution function, the
proportionality of hazard rates, the interaction between same treatment
components or between treatments and some concomitant variables, the
doubling time, the risk of nodal involvement or the risk of remote
metastases within some specified interval. To answer the question as
to whether one treatment is preferable to another one it may happen
that
(i) different answers are given according to how the question was
specified (and what model was adopted);
(ii) a difference of treatment effects, even though substantial, is
hard to interpret in terms of a "better than" relation;
(iii) a significant difference of treatment effects is undetectable
because some internal observations, such as response, were not
available.
I will not enter now into a debate of principle on comparative stati
stical inference. I would rather want you to bear in mind that we must
not describe the result of a trial in terms of simple statements of
significance levels or interval estimates. Treatment effects are not