CancerGuide: Researching Your Options
What are "Endpoints" and Why are they Important?
Oncologists use the term endpoint to refer to an outcome they are trying to measure with a clinical trial. Understanding endpoints is absolutely critical to understanding the technical medical literature. All journal articles reporting on clinical trials will report the results in terms of the endpoints which were measured. If you don't understand what they mean, you can't understand the article.
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.
Capsule Summary of Endpoints
Detailed Description of Endpoints
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.
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:
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
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.
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.
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.
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").
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).
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:
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.
Quality Of Life is often abbreviated QOL or QL.
The Functional Assessment of Cancer Therapy scale: development and validation of the general measure.
J Clin Oncol. 1993 Mar;11(3):570-9.
Comment: This is the original paper on the development of the FACT Quality Of Life Questionnaire.
This CancerGuide Page By Steve Dunn. © Steve Dunn
Page Created: September 14, 2004, Last Updated: September 14, 2004