Critica Sistemas de Medida
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Transcript of Critica Sistemas de Medida
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232 NEWS Journal of the National Cancer Institute, Vol. 98, No. 4, February 15, 2006
N E W S
Criticism of Tumor Response Criteria Raises
Trial Design Questions
When it debuted in 2000, the Re-sponse Evaluation Criteria in Solid
Tumors (RECIST) was intended to be a
simpler way to measure the response of
tumors to experimental treatments. (See
article, Vol. 92, No. 3, p. 205.) The prior
criteria, adopted by the World Health
Organization in 1979, involved a com-
plicated formula that required measuring
two dimensions on a tumor and multi-
plying the parameters with a calculator,
if not a computer. RECIST made the job
easier by requiring measurements of just
the longest dimension of several tumorsand adding them together.
But, in the 5 years since the wide-
spread adoption of RECIST, the mea-
surement tool has drawn some criticism.
Critics argue that the RECIST criteria
are too narrowthey force researchers
to say a drug works or does not work
based solely on changes in tumor size.
In addition, some researchers say the
criteria arent universally applicable to
all cancer types and drug classes andresult in too many single arm phase II
studies that are not predictive of a drugs
ultimate success.
Although there is room for improve-
ment within some of the criteria, much
of the blame
directed at
RECIST is re-
ally misplaced
frustration
about poor clin-
ical trial design,
says ElizabethEisenhauer,
M.D., who dis-
cussed this and
other issues
that have arisen
in the 5 years since the RECIST criteria
were published at the European Cancer
Conference in Paris in November.
People confuse the problem re-
lated to design and choice of endpoint
with how you measure tumors, saidEisenhauer, vice president of the
National Cancer Institute of Canada
and a co-author of the RECIST criteria.
So they believe that using response
criteria means using the same design
regardless of the agent and tumor type.
They feel they need to show the same
degree of response in noncytotoxic
drugs that might be seen in traditional
cytotoxic drugs, but no part of RECIST
states a minimum response rate that
is important for declaring interest in a
new drug.In other words, researchers can de-
cide that, for example, a 10% overall
response rate or a 50% stable disease
rate in a particular trial is meaningful,
but to determine what that response rate
or stable disease rate is, they still need
to measure tumor loadand for that,
RECIST criteria are available.
We dont need a new way of de-
scribing what can happen to a tumor,
Elizabeth Eisenhauer
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Journal of the National Cancer Institute, Vol. 98, No. 4, February 15, 2006 NEWS 233
Eisenhauer said. We need a new way of
designing the trial using those categories
that signal activity for drugs that might
not cause tumor shrinkage.
Shrinking Interest in Tumor
Shrinkage?
The RECIST criteria have become afocal point of discussion in the trial de-
sign debate because of the underlying
and traditional assumption that patients
can be categorized into responders and
nonresponders based on changes in the
size of their tumors. That belief leads to
insistence that tumor response be a part
of clinical trial testing.
The contentious point is that some
people believe active agents shrink
tumors no matter what, said Gwen
Fyfe, M.D., vice president of hematol-
ogy and oncology at Genentech. It
seems less likely that targeted agents
will shrink tumors, but clearly some of
them do.
To some, this stems from the
traditional way that clinical trials test
new therapies in patients with tumors
with a phase II clinical trial using a few
patients who are treated with a single
agent alone. In single-arm trials, they say,
tumor response rate has to be used be-
cause of the belief that tumor regression
is the surest measure of a drug effect.But several cancers are not easily
measurable in such a phase II setting.
For example, Howard Scher, M.D., pub-
lished a study last July in Clinical Can-
cer Research that found that few patients
with metastatic prostate cancer had tu-
mors that were measurable according to
RECIST criteria, and that there are no
target lesions in patients with rising PSA
and localized disease, making these pa-
tients ineligible for trials that use
RECIST criteria.
In short, most prostate cancer justdoesnt spread in a way that allows tu-
mors to be measured, said Scher, chair of
urologic oncology at Memorial Sloan-
Kettering Cancer Center in New York.
Therefore, RECIST misses the point.
What you really want from a clinical
trial is a decision on whether an agent
worked, and to what degree, and in pros-
tate cancer, I dont see how RECIST can
get you there, he said.
Scher agrees with Eisenhauer that the
real problem is that investigators dont
state clearly what their expectations are
and what outcome of a trial would con-
vince them there is enough signal to go
forward, Scher said. One size doesnt
fit all, and you shouldnt design a trial to
serve the criteria but [instead to serve]the endpoint that is based on what you
are trying to show.
Controlling Comparisons
In fact, argues Mark Ratain, M.D.,
from the University of Chicago, re-
sponse criteria havent even worked for
our current drugs. Ratain, a well-known
critic of oncology clinical trial drug de-
sign, says that our current criteria are
not useful to predict drug approval. In a
recent editorial in Clinical Cancer Re-
search, Ratain wrote that positive phase
II trials have not been predictive of
phase III success because very few
drugs that go into phase III testing are
found to show benefit.
Conversely, if tumor change is the
only criterion used in phase II testing,
then effective agents such as Herceptin
(trastuzumab), Tarceva (erlotinib), andAvastin (bevacizumab) would never
have been approved because of their
fairly low response rate of about 10%,
he said.
Ratain is pushing for larger phase
II studies that use a control arm that
can truly detect treatment differences
between groups. Current metrics
are all designed with single-arm trials
where you have to say how many
people responded because you dont
have a control group, he said. You
need a control group to compare apples
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234 NEWS Journal of the National Cancer Institute, Vol. 98, No. 4, February 15, 2006
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and apples. You can still use some stan-
dard metrics to compare apples and
apples, but you can also use any metric
you want to compare, such as disease
stability, time
to progression,
or quality
of life.He notes
that other dis-
ciplines use
randomized,
controlled
phase II trials.
Oncologists
are the only
ones that use
uncontrolled single-arm phase II trials,
and we only do it that way because it is
our religion, the way we were trained to
do it, Ratain said.
Robert Glassman, M.D., a New York
oncologist and investment banker, notes
that only three to five oncology drugs are
approved each year, although 635 drugs
are currently in human testing and more
than 2,000 are in discovery or preclinical
testing, mostly in the United States.
Phase II should be the place where
drugs are filtered out, but most noncon-
trolled studies, which are filled with bi-
ases, have proven not to be predictive,
he said. Only overall survival and qual-ity of life are true, clinically meaningful
endpoints. Everything elseresponse
rate, progression free survival, time to
progression, etc.are surrogates.
Progression-Free Survival
Ratains trial design of choice is a ran-
domized discontinuation design in which
patients with stable disease are treated
with an agent and then randomly as-
signed to continue or to go on a placebo.
Results are then compared. If stable dis-
ease is a criterion, then you can defi-nitely measure between the groups to see
if this is meaningful, Ratain said.
Ratain cites tests of two different re-
nal cancer agents, carboxyaminoimid-
azole (CAI) and sorafenib. Both showed
a RECIST response rate of 2%, but the
randomized discontinuation design used
in both trials showed CAI to be nonac-
tive, whereas sorafenib demonstrated
substantially longer progression-free
survival. Sorafenib is a highly active
drug that was approved even though it
doesnt have much of a response rate,
he said. But how would you find this
out if you are using response rate as a
screening criterion? Both are either ac-
tive or inactive depending on what you
believe 2% represents.Response rate is prone to patient
selection bias, especially as the drugs are
tested in earlier disease, said Genentechs
Fyfe, and in the end, response rate only
tells you something about the 20%, say,
who might have had some objective
measure of tumor shrinkage.
But it doesnt tell you what hap-
pened to the other 80%, she said. Did
the drug affect them and slow the pace
of their disease? Did it cause a little bit
of tumor shrinkage but not enough to
meet RECIST? When you just look at
response, it is an arbitrary dichotomous
variable that ignores all the people who
didnt get an objective response, and
those people may or may not have ben-
efited in the pace of their disease.
Genentechs favored criterion is
progression-free survival, because pro-
gression in each patient in a trial can be
measured against that of other patients,
and each patient is valued equally in a
progression analysis, Fyfe said.
Eisenhauer said that the oncologycommunity should have a discussion
about these design issues but added that
phase II control arm studies require
many more patients than the usual
single-arm trial, which raises some
issues about feasibility.
Still, she points out that if progres-
sion or even tumor stability are chosen
endpoints for these studies, it will still
be necessary to use RECIST to quantify
those variables. RECIST is just a com-
mon language for describing what is
happening to patients on trial who havetumor masses at baseline when they start
on treatment, she said. RECIST
brings up all kinds of issues because I
think people are really looking for some-
thing magical that will tell them for sure
what drug will work and what wont
work. At this point, we dont have any
guaranteed formula for that.
Renee Twombly Oxford University Press 2006. DOI: 10.1093/jnci/djj086
Mark Ratain