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CHAPTER IX
INTRODUCTION TO CLINICAL STUDIES
CLINICAL STUDIES OF ANTINEOPLASTIC AGENTS
PHASE I, PHASE II AND PHASE III STUDIES
The purpose of clinical experimentation in
oncology is to explore and design better
methods of treat ment for those patients
with cancer.
The majority of the drugs currently in use
as antineoplastic agents have passed through
the different stages of research mentioned
below:
1. Extraction and purification.
2. Toxicological and antitumoral studies
in animals.
3. Manufacture of useful formulas.
4. Toxicological studies in large
species (dogs or monkeys).
5. Studies for clinical evaluation.
Phase I Studies
After determining antitumoral activity in
acceptable dosages and determining the safe
dosage with which clinical research can be
initiated, Phase I studies can be begun,
having as goals:
1. To establish the TOLERABLE TOXIC
DOSAGES in accordance with different
forms and schedules of administration.
2. To establish the standards of
toxicity and determine if toxicity is
predictable, tolerable and reversi ble.
3. To establish the pharmacological
effect of the substance in humans which
is principally explored from a
toxicological point of view to determine
its therapeutic value.
What frequently happens is that these
studies include patients who, having failed
with conventional treatments such as
surgery, radiation and chemotherapy, are
still in such physical condition as to allow
them to be monitored and complete a
satisfactory evaluation of the toxicity of
the substance being studied. Other patients
for whom there is no currently useful, known
treatment are also included.
Concerning ethical aspects, it must be
mentioned that the study is considered
justified if the sub stance being studied
has shown promising antitumoral activity in
animal tumor models and that the pa tients
truly belong in the category mentioned
above. However, patients should always
receive the benefit of adequate medical
attention that avoids and resolves the
undesirable side effects that might be
caused during the use of the substance being
researched.
It is customary to initiate these studies
with one third of the MINIMUM TOXIC DOSAGE
found in dogs, for each of the methods which
may be used.
The attempt should be made to reach the
MAXIMUM TOLERABLE DOSAGE in each which is
con sidered to be an adequate and effective
form.
A wide variety of tumoral types should
always be included, since the tolerance and
effectiveness of the substances can be
different in accordance with the tumor
types.
Phase II Studies
These are designed to determine the
antineoplastic activity of the substances
upon various tumor types.
Dosages and therapeutic schedules designed
according to the findings in Phase I studies
are generally used.
The most important thing for an adequate
evaluation of the response of the patients
to the sub-stance under investigation is to
include well defined and measurable criteria
concerning OBJECTIVE RESPONSE. It is
accepted that the dimensions of the tumor,
calculated by diverse methods and the sur
vival time of the patients from a well
defined point of time (the date of the
diagnosis, the date of the first treatment,
etc.) are the parameters of tumoral response
that best satisfy the criteria mentioned
above. If is also useful to evaluate each
one of the named parameters in accordance
with their duration (it is ac cepted that
for COMPLETE AND PARTIAL REMISSIONS the
minimum duration period should be one
month), even though in the evaluation of
survival time this becomes problematical as
the patients can die from causes not related
to their cancer or because of toxicity of
the medicines being studied. On the other
hand, the complete evaluation of survival
time cannot be completed until the patients
on the study die.
There are two types of Phase II studies. In
one, the antineoplastic effects of the
substance is ana lyzed in a universal manner
and for that, a large number of patients
with a sufficient variety of histological
types of malignant neoplasms are included in
the study, even though in each group the
number of pa tients is small and the
analysis which can be made of the different
prognostic factors that may influence in the
response of each type of tumor to the
substance is very limited (for example the
functional capaci ty, the histological type,
the degree of suffering, etc.).
Nevertheless, it is indeed possible to
determine if a substance has antitumoral
effect by this method and also, in which
tumoral types it demonstrated the greatest
antineoplastic effect. Sometimes, it is also
possible to report some of the factors which
had a positive or negative influence in the
response.
The second type of Phase II studies is
oriented toward investigating the
therapeutic effect of an agent upon specific
groups of patients, taking into account the
different PROGNOSTIC FACTORS that in fluence
the response, and specifying in the study
protocol, the requisites that the patients
should have in order to make analyses which
are comparative and evaluative in nature.
In these studies, it is sufficient that the
protocol be well defined in order to receive
valid results and it is not necessary that
the patients be randomized.
Frequently, in the Phase II studies, not
only is the antineoplastic activity of an
agent determined, but also which treatment
schedules are the most useful and tolerable.
So, even with a relatively small number of
patients, valid conclusions may be drawn.
Phase III Studies
The Phase III studies are always comparative
and are designed to evaluate the
effectiveness of a therapeutic scheme in
comparison to another or others already
accepted as being effective.
The condition sine qua non is that
the patients included in each of the groups
to be compared, have similar characteristics
and prognostic factors or comparable
determinants of the response, thus avoiding
as much as possible the influence of factors
not related to the effect of the substance
and the schedules being studied. Only those
patients who received the minimal dosages
and number of treat ments which will make
the response worthy of evaluation in a
uniform, adequate manner are included in
these studies.
One of the patient distribution systems
which permits better results is that one
called Randomiza tion and
Randomization-Stratification. In the first,
the patients are distributed by a computer
in a pre determined manner into each one of
the groups of patients to be compared. The
inconvenience of this system is that by not
including a large number of patients in each
group, there is a great risk that the
multiple, individual factors of the patients
may not allow these groups to be truly
comparable. In the se cond case, that of
Randomization-Stratification, the attempt is
made to avoid some of the problems of the
previous system by randomizing the patients
after classifying and stratifying them in
accordance with the principal, prognostic
factors concerning the malignant tumor to be
treated and with those that determine the
tolerance to the treatment that Is intended
for use.
The control groups (or those that receive
treatment now accepted as useful) may be
formed by careful selection of previously
treated patients ('historical control") or
patients treated simultaneously to the group
receiving the treatment in evaluation.
Although they are few in number, there are
still some researchers who accept as valid
Phase Ill studies which utilize historical
controls. The argument against it is that it
is almost impossible to find a comparable
group of patients even in the same
institution if the patients are treated at
different periods of time. Patients will
frequently receive different diagnostic and
therapeutic attention which will influence
the response and tolerance of the patients
to the treatments received. It is also
certain that the care and characteristics of
treatment received from different human
teams can influence the response to the
treatment being studied.
The Phase III studies must always clearly
indicate the number of patients who were
considered "candidates" to enter the study,
those who were "eligible" In accordance to
the criteria and selection methods as well
as those who were actually "included" and
those who could be "evaluated' at the con
clusion of the study.
The conclusions for the Phase I studies
generally have to do with the toxicity of
the agent at therapeutic dosages, in the
research of Phase II, with the general or
specific antineoplastic effect of the
substance and in the studies of Phase III,
with the therapeutic value of the substance
or tI~erapeutic schedule in comparison to
the treatments that were considered useful
up to that time.
BIBLIOGRAPHY
1. Staquet, M.J.. editor: cancer Therapy;
Prognosllc Factors and criterIa of Response.
New Yor. 1975. Raven Press.
2. Bergevin, P.R.; Blomm, J.; Tormey, nc.,
editors: Guide to Therapeutic Oncology.
Baltimore, 1979. williams and Wilkins Co.
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