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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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N E W S

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

N E W S

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

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