Endpoints can include all kinds of things, but this article is about the
most important kind of endpoint - those which relate to the effectiveness of
treatment, called efficacy endpoints. There are many ways to measure the
effectiveness of treatment - the endpoints I talk about here are the most
commonly used ones.
Oncologists frequently use some of the same terms in talking to patients
about benefits that might be expected from treatment. In particular, it's
common for an oncologist to estimate the chance you will "respond" to
treatment. Doctors will also use the jargon of endpoints in talking about how
well treatment is working as in, "you are responding to the treatment." Knowing
what "respond" might mean will help you know exactly what questions to ask.
Rather than just reciting a laundry list of different efficacy endpoints, I
discuss when they're used, how they relate to clinical trials (this article
partially overlaps some of my clinical trials
articles), technical details of how they're measured, and the pros and cons
of each and, of course, the associated jargon, which (surprise!) can be just a
bit thick at times.
Response and Related Endpoints
Response is about measuring tumor shrinkage. Because cancers only very
rarely get smaller without treatment, a significant tumor shrinkage shows
treatment is having an effect on the tumor. Response is usually the primary
endpoint in Phase II trials but is often measured in Phase I and III trials as
well. Response is not an endpoint for adjuvant clinical trials where the
primary tumor has been removed surgically since in that case there are no
detectable tumors to measure.
Rough Definitions of Response
This section will give you a rough view of what the different response
categories mean. There are specific technical criteria for each of these
categories which I cover later. Note that a patient's response is characterized
by the greatest amount of shrinkage they achieve from the time treatment
started. So if a patient has a major shrinkage which is a response but later
has tumor growth it's still categorized as a response. The duration of the
response is from the time response is achieved until renewed growth is
detected.
Main Categories
- Complete Response (CR): Complete response means all
detectable tumor has disappeared. If a treatment does cure some patients,
those patients will have their tumor disappear. A CR is a potential cure. If
you have advanced cancer a CR is also the best result you can actually see from
treatment. Even so, a complete response does not necessarily mean the patient
is cured. Even when no tumor can be seen on scans, there can be residual tumor
which is too small to detect, and so unfortunately, complete responses may not
last. Whether a complete response is likely to last can often be gauged by
looking at the history of the type of treatment that produced the response in
your type of cancer. In some situations very few complete responses are cures
and in others most are cures. To find out, you have to research your
cancer and the treatment in question.
A patient who has had a complete response may be said to be "NED". NED means "No
Evidence of Disease".
- Partial Response (PR): This roughly corresponds to at least a 50%
decrease in the total tumor volume but with evidence of some residual disease
still remaining. Partial responses aren't usually cures and usually aren't a
long term benefit because significant tumor remains. In some cases the residual
disease in a deep partial response may actually be dead tumor or scar so that a
few patients classified as having a PR may actually have a CR. Also many
patients who show shrinkage during treatment show further shrinkage with
continued treatment and may achieve a CR.
- Minor Response (MR): "Minor response" roughly means a small amount
of shrinkage. Minor response is not really a standard term but is increasingly
used. Roughly speaking, a minor response is more than 25% of total tumor volume
but less than the 50% that would make it a PR. A minor response is not enough
to be considered a true response, but data on minor responses may be given in
reports on clinical trials. If minor responses are not categorized then they
would be considered Stable Disease (see below). Although minor responses are
often considered insignificant, I believe that some of the new anti-angiogenic
therapies (treatments that target tumor blood vessels) which show a high rate
of minor response are likely to be benefiting patients, as long as those
responses last for a reasonable length of time. Also, of course an "almost
partial" response, is hardly different from a "barely partial response". Such
boundaries are artificial. Again with more treatment, a minor response may
evolve into a deeper response, a PR or a CR.
- Stable Disease (SD): Although stable disease intuitively means the
tumors stay the same size, to account for measurement errors on scans and to
discount "insignificant" changes, stable disease includes either a small amount
of growth (typically less than 20 or 25%) or a small amount of shrinkage
(Anything less than a PR unless minor responses are broken out. If so, then SD
is defined as typically less 25%) Because of this, slow growing tumors may be
classed as stable for quite some time, or for several scans if scanning is
frequent. Also some periods of stability are relatively common in some kinds of
cancer even without treatment. Therefore, it is difficult to know if stable
disease is the result of treatment. Claims of benefit for new treatments
involving stable disease should be examined skeptically. For more on the
difficulties of Stable Disease, see my article,
Stable Disease: A Prolematic Endpoint.
Like a minor response, stable disease is not considered a true response. At the
same time, if you are experiencing stability with or without treatment that is
better than growth. Finally, stable disease can evolve into a response with
more treatment.
- Progressive Disease (PD): Progressive disease means the tumor has
grown significantly or that new tumors have appeared. The appearance of new
tumors is always progressive disease regardless of the response of other
tumors. Progressive disease normally means the treatment has failed and in most
cases is the signal that it's time to try something else (or stop treatment
altogether if no good options remain). If you are on a clinical trial and have
progressive disease during treatment, you are likely to be taken off study (in
a few cases you may be allowed to cross-over to the other arm of a randomized
trial, or your treatment may be otherwise modified). Most clinical trials for
advanced cancer which allow prior treatment require that you have had
progressive disease since your last treatment (or in other words, that your
last treatment didn't work or has stopped working).
Summary Categories:
- Objective Response (OR): Objective response means either a partial
or complete response (In the literature you'll frequently see "CR+PR" which
means the same thing). When you see an objective response rate be sure to look
at how many are complete responses and how many are partial since benefits from
complete response tend to be greater. Often news reports and especially press
releases by self-interested companies blur this and don't reveal that the CR
rate is low or non-existent. Track down the original source and find out!
- "Clinical Benefit": Clinical benefit is an informal term which
usually means anything other than progressive disease. Use of this term is
suspect, particularly if it is in a press release or news report. It isn't
automatically clear that patients with stable disease are benefiting from
treatment since the natural history of cancer can include periods of apparent
stable disease and since tumor shrinkage is not equal to clinical benefit to
begin with. When you see this term you should look at both the CR and PR rates
and also the duration of "benefit" including for stable disease cases.
Note that you'll constantly see the abbreviations CR, PR etc in the research
literature.
Duration of Response
Cancer therapies can produce temporary responses without any lasting
benefit. On the other hand, some cancer therapies can be curative or at least
give a meaningful respite from the disease. If there are no data to show an
improvement in survival, then you want to look at responses and see how many
are lasting. If a treatment is going to make a real difference, tumor
shrinkages should last at least long enough to give a meaningful respite. If a
treatment is to cure some patients, then some complete responses should last
indefinitely. There are treatments which give a small percentage of patients
durable CRs, which may be cures. If you have a difficult cancer, then even if
survival is reported or is the main endpoint, it's worth looking to see if
there are lasting CRs (Frustratingly, they don't always report on this).
Reports on clinical trials in the medical literature commonly give not only
the number of responses, but also the duration of responses, particularly for
phase II trials where response is the primary endpoint. Some papers only
provide summary information on this but often the duration of response is given
for every responding patient.
Response duration for an individual patient is given as a number possibly
with a plus sign after it like "6+". Usually the unit is months but not always,
so you should read carefully to be sure. A plus sign after the response
duration for an individual patient means the response was still ongoing at the
last evaluation. Conversely, the lack of a plus sign means the patient relapsed
at the given time. The plus sign is anything but a minor detail - it's key to
telling whether a treatment is giving some patients lasting benefit!
Often all of the responses are listed sorted by length like:
45+, 38+, 32+, 30, 23+, 21 or
12, 8, 6+, 5+, 3+, 2+
CRs and PRs are usually listed separately.
The difference between these two examples is important. In the first there
is relatively long term follow-up and the responses are mostly holding. It's
encouraging. In the second, follow-up time is much shorter and the fact that
four of the responses are holding at six months or less doesn't really tell you
much, especially since the two slightly longer responses didn't last. Obviously
the two relapses at 8 and 12 months in this small example is not nearly enough
data to know what the range of possibilities might be, but you'd certainly want
to look hard for other options if this was the best you could find on a
treatment.
You will find that the results of early phase trials often include only
relatively short follow-up when they are first presented or published,
particularly if they're presented at medical meetings where very early results
are often presented. Naturally, this makes it hard to judge response duration.
For more established therapies, especially anything FDA approved, there should
be better data on response duration. Similarly, if a new therapy has been in
testing for a while, there may long enough follow-up that there is useful data
on response duration. This was the case for the experimental treatment which
saved me. See my article The Hint for the actual
data.
There are a few nits about measuring response duration. The duration of
response will depend two things, on when the response is counted as starting
and on when the response is counted as ending. Unsurprisingly, a response is
normally counted as lasting from the time response is first achieved to the
time progression from the best response is detected. What is a little more
subtle is that these things depend a bit on how often scans and tests are
scheduled including how close to the start of treatment the pre-treatment
measurement scan is taken. The longer response durations the, less all of this
matters.
Questions to Ask Your Doctor
If your oncologist quotes a chance of "responding"
to a proposed treatment it's worth asking some basic questions:
- Does "response" mean CR + PR? If not, what is the CR + PR rate? What is the
CR rate?
- What is the range of durations of response? Are there long term CRs?
- Is there any data to show a survival benefit from this treatment?
- If this is a local or regional treatment like radiation, how much will it
help me to have a response in only the treated tumors?
Technicalities
Measuring Tumor Volume
How tumor volume is measured depends on the kind of cancer. Most common cancers
form discrete nodules or masses. These kinds of cancer are called "solid
tumors" and there is are very standardized methods for measuring solid tumors. I talk about
response criteria and measurement of solid tumors below. After that I briefly discuss
the other cases, liquid tumors, and types of solid tumor where the standard response criteria
don't work well.
Measuring Solid Tumors: General
- Response or stable disease always requires that you have no new tumors. A
new tumor means you have progressive disease.
- Normally, a response has last at least a month or be confirmed by the next
set of scans before it counts. Often a longer duration is required for
apparently Stable Disease to count. I am seeing 6 months more and more often.
For most kinds of cancer 6 months would be a long time for there not to be
significant growth if treatment weren't having an effect. Watch out for early
reports, especially meeting presentations (and those ever-spinning press
releases), which don't specify how long counts as stable or which don't have
any minimum to count as stable.
- Individual trials can have differing definitions of response. Any clinical
trial report in the technical literature will describe what those criteria
were. Often this is just referenced as the standard WHO or RECIST criteria (see
below) but sometimes more details are given.
- Blood markers like PSA for prostate cancer or CA-125 for ovarian cancer are not
used as a substitute for measuring tumor masses in the standard cases. If there
is a standard blood marker for your cancer, your levels must return to within the
normal range for you to be declared to be in complete response. If the standard
response criteria don't work well for your type of cancer and there is a standard
blood marker, it will probably be used in constructing response criteria for your
kind of cancer.
Measuring Solid Tumors: Measurable Disease
In order to quantify tumor shrinkage, it is necessary to be able to
accurately measure the size of the tumor using scans or physical exam in a few
cases. Most metastases can be accurately measured but some types such as bone
metastases and accumulations of fluid caused by tumors (called effusions) are
not considered to be measurable (this is not a complete list of non-measurable
tumors). A measurable tumor usually has to be at least a minimum size such as 1
centimeter in diameter.
You may have both measurable tumors and non-measurable tumors. For instance
you might have measurable lung metastases and bone metastases. If you have at
least one measurable tumor then you have measurable disease.
Measurable disease is required in any trial where response is a primary
endpoint. Phase II trials which usually have response as the primary endpoint
normally require measurable disease, and phase III trials sometimes do. Phase I
trials usually do not require measurable disease. Since the criteria for
measurable disease can be technical, if you are considering trials which
require measurable disease, please discuss whether you have measurable disease
with your doctor if you have any doubt.
Measuring Solid Tumors: WHO Criteria Versus RECIST Criteria
You may sometimes hear partial response described as a 30% shrinkage instead
of a 50% shrinkage. So when is 30% equal to 50%? Well when there is only one
dimension considered instead of two.
The older standard for response, the WHO (World Health Organization)
criteria, defined a shrinkage of a tumor as the decrease in the product of the
largest perpendicular diameters in the largest "slice" of the tumor on a scan.
This defines the area of a square and is proportional to the area of a circle
(a more likely cross-section of a tumor). Measurable disease under this system
is called "bidimensionally measurable".
The newer standard, the RECIST criteria, defines a tumor's shrinkage as the
decrease in the length of its largest diameter. This is called
"unidimensionally measurable". This makes measurement easier and has been shown
to be as good as measuring in two dimensions.
It turns out that on average, a 30% reduction in one dimension is the same
as a 50% reduction in the product of two dimensions. If you had a circle and
its diameter shrunk by 30%, as in the RECIST criteria, then the product of two
perpendicular diameters as in the WHO criteria would shrink by 49% which is
close enough to 50% (100% x (1-.3)2 = 100% x
0.72 = 49%). Anyway, the main point here is that the two
systems give very close to equal results.
Note that actually tumors have three dimensions so a partial response in
either system actually means more than a 50% reduction in tumor volume.
Special Tumor Types
Some kinds of cancer require different definitions of response. This
includes blood cancers like the leukemias which don't form solid tumors. It
also includes a few other kinds of cancer such as prostate cancer which
predominantly metastasizes to the bone, or such as multiple myeloma which
starts in the bone. As I mentioned about bone tumors aren't considered
measurable. In all of these cases the broad concept of response is still
similar to the rough categories I've given above.
If you have one of these tumors, you will need to learn what the criteria
are for response in your specific cancer. You'll pick it up as you read papers,
from your own experience as a patient, and from the basic information on your
cancer which is likely to talk about any specialized tests particular to your
cancer. There may or may not be standardized criteria, and you may also find
that definition of response incorporate blood marker tests like PSA for
prostate cancer, or incredibly sensitive DNA based tests for finding cancer
cells in some types of leukemia.
Resources
- RECIST Criteria Quick
Reference from the US National Cancer
Institute.
-
Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L,
Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG.
New Guidelines to Evaluate the Response to Treatment in
Solid Tumors
Thoughts about Response
It's often emphasized that tumor shrinkage is not in and of itself a benefit
to patients - only to the extent that it relieves symptoms or improves
survival. While this is true, I also think that tumor shrinkage is extremely
important.
Although tumor shrinkage may not be proof that a treatment is truly
beneficial, if a treatment really is beneficial one expects at least it will
stop the cancer from growing. If a treatment cures some patients one expects
that all detectable cancer will disappear under treatment for cure patients.
Also if tumors shrink and this effect lasts for a significant amount of time it
is likely the patient has gotten a benefit.
Unlike other endpoints, response shows treatment has a direct biological
effect on the cancer. Unlike survival related endpoints, response does not
require randomized trials to demonstrate that the treatment is having an
effect. People survive various lengths of time with no treatment, but tumors
only very rarely go away on their own.
Knowing that a treatment creates response in advanced cancer supports
positive results for trials adjuvant therapy using that treatment. Positive
results with an adjuvant trial with a marginal "p value" (To understand p
values see my article, The Significance of
Statistical Significance) might still be due to chance. Knowing the
treatment is biologically active should add some confidence in the results.
Documentation of response also buttresses and clarifies results with
survival related endpoints in advanced cancer. A treatment which at best slows
the growth of the tumor and doesn't even create stable disease is surely a weak
treatment. A treatment which does not give complete responses is not curing
anyone.
If you have advanced cancer which has no good treatment and are looking for
new and promising therapies you may very well need to rely on phase II trial
results which have response as an endpoint. Phase III trials to prove survival
take a long time to conduct and phase II results will be available much sooner.
If there are complete responses and if responses appear to be lasting this is
real evidence the treatment is helping some patients, even if there is
uncertainty.
Survival
Improved survival is a major goal of cancer treatment (Cure is the
goal!). Survival is therefore a very important endpoint in cancer trials and is
one which, unlike some other endpoints is a direct benefit to patients.
Because showing an improvement in survival requires comparison to a control
group, survival is a primary endpoint in Phase III and Adjuvant trials. These
trials are normally randomized so that the survival of comparable groups
treated with different treatments can be compared. Survival is normally
reported using survival curves. See the Statistics
Section for several articles on these important curves.
Thoughts on Survival
Survival is technically easy to measure unambiguously and objectively since
there is nothing subjective about the date someone dies. This is an advantage
over endpoints like response or progression free survival which require
measuring whether the tumor is growing as well as how long they live. Survival
also accounts for any long term increase in the death rate due to long term
side effects even if they are unrelated to acute side-effects.
In situations where long term survival is common, measuring survival
differences may take a long time. There is a risk that ideas, technologies and
treatments will have improved by the time the results are in. Survival always
takes longer than progression-free survival (see below) to measure.
When you see positive results from a survival trial, it's important to ask
whether the trial is actually increasing the cure rate or whether instead it
extends life without increasing the cure rate (An increase in cure rate will
result in a higher plateau on the right tail of the curve). If the treatment
improves survival without improving the cure rate, you want to know the likely
and possible benefits. Not infrequently a big deal is made out of treatments
which improve median survival by only a few weeks or months. But what may be
lost is whether some patients get a much larger benefit and survive years
longer than they would have. The best way to answer these questions is to look
at the survival curves. For much more on this, look at my articles on survival
curves in the Statistics Section.
Measuring survival in a randomized trial for advanced cancer requires that
patients given one treatment who progress cannot be allowed to try the other
treatment (switching arms is called cross-over). This may not be
perceived as a disadvantage by those who design trials, but it most certainly
is by patients whenever denying cross-over denies them any additional hope that
might come from trying the other treatment. Although cross-over isn't allowed
in these circumstances, ethical considerations normally require that patients
who have advanced disease be permitted to seek out other therapy of their
choice. This actually is a scientific disadvantage since the results may be
blurred or even biased by treatments chosen later. Note that if the endpoint is
progression free survival (see below) then cross-over can be permitted.
Finally, historical or concurrent non-randomized controls have very
low-standing because they are subject to bias. For instance, improvement in tests
for detecting recurrence which result in finding recurrences sooner can make it
look like more recent patients live longer after a diagnosis of recurrence.
Concurrent non-randomized controls suffer from all kinds of possible bias
related to characteristics of patients who choose (or are referred to) one kind
of treatment versus another. For instance, more motivated and stronger patients
might choose to travel for a difficult experimental treatment compared to those
who came from the local area and took the standard treatment. Patients with
those characteristics might well live longer than others even if the new
treatment is actually no better than the old. A closing thought: Almost every
intelligent layman I have ever talked to comes up with the idea that with
rigorous recording of treatment results and patient characteristics, the need
for expensive (twice as many patients), and sometimes ethically uncomfortable
randomized trials could be eliminated. I believe the dogma of the randomized
trial inhibits efforts to find a better way.
Jargon
Progression Free Survival and Disease Free Survival
Progression Free Survival is the length of time you are both alive and free
from any significant increase in your cancer (free from progression). Progression is
defined the same way as I described under response.
Disease Free Survival
Disease Free Survival is a special case of Progression Free Survival used as an
endpoint in the clinical trials of adjuvant therapy to prevent recurrence after
surgery to completely remove all visible cancer. In this case "progression"
means the patient has had a recurrence.
Thoughts on Progression Free Survival and Disease Free Survival
Like survival, these endpoints normally require a randomized trial to
measure. An improvement in progression free survival isn't guaranteed to
translate into an improvement in survival although I think it usually does.
For adjuvant therapy, if the same treatment works to some extent in
recurrent cancer, the question arises whether treating patients after they
relapse is just as effective. The hope is that treating when there is so little
cancer that the patient appears to be free of disease will be more effective
than treating when there are large detectable tumors. In some cases this has
proven to be true. If adjuvant treatment appears to improve the cure rate when
the same treatment doesn't cure in relapsed patients, it's a win. Because no
one knows for sure who will relapse, adjuvant therapies usually mean treating
some patients who are already cured. The disadvantage of that increases the
more likely it is that the patients who are treated are in fact already cured,
and the more toxic and expensive the adjuvant therapy.
Progression free survival and disease free survival can translate to an
improvement in quality of life since symptoms from the cancer are delayed - but
only if side effects of treatment aren't worse.
Also unlike trials with a survival endpoint, randomized trials in metastatic
cancer which measure Progression Free Survival can allow cross-over on
progression if it makes sense. In adjuvant therapy trials cross-over doesn't
make sense, since patients get only one adjuvant therapy and are treated for
recurrence if they relapse.
Both of these endpoints are subject to some uncertainty compared to plain
survival because determining that there is progression or relapse involves
reading scans, which always has some associated uncertainty. Doing these trials
well requires a rigorous schedule for testing, and a rigorous protocol for
examining the scans and declaring a relapse. This includes reading of the scans
at a central location by radiologists who are not told which treatment the
patients got (the radiologists are said to be "blinded").
Jargon Summary
- PFS: Progression Free Survival
- DFS: Disease Free Survival
- RFS: Relapse Free Survival
Quality of Life
Quality of Life is supposed to measure how you feel and how you function.
Although quality of life is certainly important in the broad sense,
unfortunately, there is no unambiguous physical measurement or definable
property which corresponds to your "Quality of Life". Quality of Life is
therefore measured using a brief questionnaire in which patients rate their
ability to function in various ways and enjoy life. Patients typically fill out
the questionnaire several times during the course of the trial.
Quality Of Life is typically measured in Phase III trials or Adjuvant Trials
and it is typically a secondary endpoint, less important than survival related
endpoints.
The most commonly used questionnaire is called the Functional Assessment of
Cancer Therapy (FACT) scale [Cella 1993], and there are
specialized FACT questionnaires for several different types of cancer (which
tend to affect quality of life in different ways).
Technicalities
The FACT questionnaire was constructed (very roughly here) by surveying
patients and also doctors about what is important to quality of life and then
constructing test questions which were evaluated by patients. The resulting
questionnaire was then tested in several ways for validity, such as comparing
results to other measures of Quality Of Life.
The FACT questionnaire asks you to indicate how true statements are for you
in five different life areas:
- Physical Well Being
- Sample Test Statement: "I have a lack
of energy."
- Social/Family Well Being
- Sample Test Statement: "I am satisfied
with my sex life." (Honestly!)
- Relationship With Doctor
- Sample Test Statement: "I have
confidence in my doctor(s)."
- Emotional Well Being
- Sample Test Statement: "I feel sad."
- Functional Well Being
- Sample Test Statement: "I am able to
work (include work in home)."
Thoughts on Quality of Life
Quality of Life is a much fuzzier endpoint than the others and that doesn't
sit well with me. It seems most appropriate for helping to decide whether a
treatment with side effects which has only modest benefits is worth doing,
especially if the treatment is taken for as long as it helps, as is common with
many treatments for advanced cancer. Quality of Life also seems appropriate for
judging the cost in quality of life of adjuvant therapies which often make
people sick who are apparently fine in the hope of increasing their prognosis
for the future. If any treatment is extremely beneficial and doesn't need to be
taken indefinitely, I think there is much less reason to be concerned with how
much quality of life is affected during treatment.
Quality of Life is determined by two main variables, the side effects of
treatment, and symptoms of the disease. Intuitively, a treatment which is
highly effective against cancer is likely to improve quality of life by
preventing or relieving disease associated symptoms. Similarly, the side
effects of treatment obviously affect your quality of life. In a sense, this
measures the tradeoff between the adverse effects of treatment and its
benefits.
The timing of side effects and benefits is also important in Quality of Life
Measurements. If the treatment really works, it will have long lasting
benefits. It may have only short term side effects in which case it's hard to
imagine a way to balance the chance of a long term benefit against the acute
side effects. This is less of a problem if the benefits are temporary or if
there are long term side effects. In essence, really good treatments - those
that are highly effective without bad side effects, obviously improve Quality
Of Life and you don't need a questionnaire to know it. Problem is there aren't
enough of those!
Finally, keep in mind that while a very honest effort was made to make the
questionnaire reflect the values of the average patient, you are not the average
patient. You very likely will have either more or less severe side effects from
any treatment than average and will react to them either more or less than
average. You don't have average symptoms from the disease either, and not only
that, you won't get the average benefit from the treatment either. Therefore,
Quality of Life tradeoffs can give only a rough idea of how you might
feel about the same treatment. Normally, you can get a similar feel for this
just from the reported severity of the side effects of the treatment and the
extent of benefit as estimated by other endpoints.
Jargon
Quality Of Life is often abbreviated QOL or QL.
Reference

Cella DF, Tulsky DS, Gray G, Sarafian B, Linn E, Bonomi A, Silberman M,
Yellen SB, Winicour P, Brannon J, et al.
The Functional Assessment of Cancer Therapy scale:
development and validation of the general measure.