Welcome back to An Introduction to Breast Cancer. I'm Dr. Neese Chadbar. I'm so pleased to have you with me today. This is one of my favorite topics. Over the last several sessions we've talked a lot about breast cancer and in each module we've talked about clinical trials. Why? Because clinical trials really are the foundation, the building blocks, that we use to make treatments better. Let's look more at clinical trials. Let's get started. So one question that patients often ask and indeed many of you may ask is, why bother participating in clinical trials? Aside from the fact that this is Doctor Chadbar's most favorite thing ever. Well there are a few good reasons. The first is, that we know that patients who participate in clinical trials tend to do better that patients who don't. Why is that? Well if you think about it, it makes intuitive sense. We're always comparing standard of care to what we think is better. So if you average things out, on average, people participating in clinical trials tend to do better. So just for selfish reasons alone, there's a good reason to participate clinical trials. On top of which, often times this is the only way that you can get the most novel therapies today. These are going to be things that become standard of care tomorrow and you can avail yourself of them early. Now the second reason to participate in clinical trials is really altruism. And many patients participate in clinical trials for exactly this reason. They know that clinical trials today are what really lay the foundation for better therapies tomorrow. So while clinical trial may not be of direct benefit to you, it may be of benefit to other people down the line. Now, one key concept is that inclusiveness is key. It's really important for everybody to participate in clinical trials. Why is that? Because if people who are like you don't participate in clinical trials, when we start using the data from those clinic trials across populations we really don't know whether there is external generalizability. That is to say, if you had a clinical trial based on a bunch of old white men, does that therapy still work on young African American women? We've seen this in other diseases like heart disease and the same thing plays out in breast cancer. So when we think about novel therapies, you really want to include everybody in these clinical trials, so that those results can then be generalized to the entire population. I love this cartoon that says we have studies of fruit flies and men, and hamsters and frogs and monkeys, but medical research with women, just hasn't occurred to anybody. Well, we need to be thinking about widespread populations and getting everybody involved. Now, let's talk specifically about phases of therapeutic clinical trials. Oftentimes, when I've referred to clinical trials, I've meant therapeutic trials. That is to say, trials that have an end point of either recurrence or survival. Now, you'll often hear people talking about phase one trials, or phase two trials, or phase three trials, and you may wonder, what are all of these phases? Well let's break it down. So phase one trials tend to be small trials, often with only a handful of patients, and really looking at the safety of a particular drug device agent. It's really about novel therapeutics. Is this something that we can use? So we tend to use phase one trials in that setting. Now phase two trials are trials that use the data from phase one trials after we have an agent that we know is safe and then we want to know, is it effective? And is it effective in this particular cancer type? So, if I have a novel agent that may have been shown to be safe in cancer, is it really effective in breast cancer? That's phase two trials. They tend to be a little bit larger than phase one trials. But most of the trials we've talked about in this session are really phase three trials. Phase three trials tend to be large, randomized controlled trials, where we're comparing standard of care, to what we think is better. After we already know what is the right dose, that it's safe, that it's effective, but is it better than what we already have? That's what a Phase three clinical trial answers. Now, clinical trials are not always just therapeutic, randomized, clinical trials. There are a number of studies that patients can participate in. So there are specimen studies. These are often studies where we are looking at biomarkers, prediction studies. Can I tell what it is in this particular cancer that makes it behave in a certain way. That information is critical, but it doesn't always require a randomized control trial. What about prevention trials? Remember back to when we talked about prevention early on? We talked about some of these prevention trials. Trials of large populations, giving them one agent versus another, or perhaps placebo to see whether an agent can actually prevent cancer from ever occurring. And then there are surveys and questionnaires. These are important too. They may not get to the endpoint of recurrence or survival, but they can often ask about quality of life. Patients reported outcomes as we often call them or PROs. Important end points. And so, it's important that you don't ignore all of these other kinds of studies as well. A few things you should know. First, studies have significant regulatory oversight. Historically, people may have had some trepidation about participating in clinical trials. They may be wary about being used as a human guinea pig and whether there's some ulterior motives for researchers. You should know that these days, when research is conducted, there are a number of layers of research oversight, that really make sure that there's integrity on the part of the researchers, and that the studies are being conducted according to good clinical practice. So being used as a human guinea pig is often not a big consideration. So know that there is oversight. The second key consideration is that you can always withdraw. So let's say your participating in a clinical trial and for whatever reason you change your mind. Oftentimes in the informed consent form, you'll see a paragraph that says something to the degree of, at any point during this clinical trial, you can withdraw. And that does not affect the treatment that you'll receive in terms of good clinical practice. So know that you're always in control. And, at any point, you can say, no thank you. Now, we always hope that you're going to participate in these clinical trials right to the end, because that allows us to get as much information that really helps us to provide the best care for future generations. But know that you have some control. Now the third consideration, particularly for people living in the United States, is with regards to the Affordable Care Act. Now some people were always a bit concerned about whether insurance would cover their usual care when they participate in a clinical trial. Or whether their insurance company would say, sorry, when you're in the clinical trial, you bear the costs. Even though many of those costs may be costs that they would've otherwise had to incur as part of usual care but then would've been born by their insurance company. Well, the Affordable Care Act mandates that that usual care has to be covered by your insurance. So there should be really no reason not to participate in the clinical trial from a financial standpoint. Now, here's a website that I want everyone to go and check out. It's www.clinicaltrials.gov. It's a great website and all of the clinical trials that are conducted, in this country anyways, must be registered on this website. It's a great website to go to and you can search based on where you are, your location or the particular disease entity that you want to look at or whether it's currently accruing patients or not. Remember, that when you think about the fact that patients do better on clinical trials, it's nice to see whether there's a clinical trial that they can participate in that's close to where they live. This website can help you to figure that out. There's a lot of verbiage that goes into clinical trials. We talk about randomized controlled trials, and IRBs and placebos. Well let's break down what some of these terms mean. First, an IRB. IRB's are Institutional Review Boards. That's part of that regulatory oversight. So any time there's a clinical trial, it is alway under the domain of the Institutional Review Board. That review board is looking over that clinical trial, making sure that patients are not getting adverse events. All of those have to be reported to the IRB. The IRB is going to make sure that this is done with diligent care, that there's oversight on these clinical trials. IRBs make sure that you as patients are safe and that the researchers have integrity in terms of the design of their studies. Placebo, this is a word that often gets people pretty scared. For many people they think of this as a sugar pill, and they often wonder my goodness I don't want to be in a clinical trial if I could potentially be getting a sugar pill. But remember that the trials that involve placebos, are often trials that compare standard of care to something better. And sometimes standard of care is doing nothing. Well it would be pretty hard to blind people to whether their getting nothing or something unless we give them something in the standard of care arm. That's where sugar pills or placebos come into play. Randomized controlled trial, taking a group of patients and randomizing them. That is to say by flip of the coin putting half the patients in one group and half the patients in another. Why is randomization so important? It's important because it makes sure that all of the other factors that we sometimes don't think about are evenly distributed between two groups. If you look at some of the trials that we've talked about during this course and you look at those tables, where they show you the two groups, you'll often find that many of the factors, the demographics, the age distribution, the stage distribution, are by magic, it seems, evenly distributed between two groups. That's the magic of randomization, it's really quite cool. But that allows these two groups now to be pretty much even, so that you know that the differences that you see are really based on the treatments that you're giving to the two groups. Double blind, what does that mean? It doesn't mean that your investigators are actually wearing blindfolds, but it does mean that the investigators don't know, necessarily, which arm you're in and neither do you. And that way you really eliminate a lot of bias. It maybe if an investigator knew that you were on a particular arm or you knew that you were in particular arm that you might have some feeling that you were going to do better or worse than the other arm. But we want to take out that bias and so if we don't tell you which arm you're in you're really at equal pose and you don't know whether you are biasing results or not. So it's another way to keep everything safe. Stratified, often times we'll use stratification, so kind of taking out groups of patients and looking to make sure that particular groups are evenly distributed. So we'll stratify based on stage or we'll stratify based on age, so that we'll get the same number of old people and young people in both arms of a trial. Stratifying before we randomize. Now, we've talked about how important clinical trials are, but often times these require many, many patients. So how do we get many, many patients in a clinical trial? There's a few mechanisms. One is cooperative groups. These are groups of oftentimes large bodies that pull together many centers. Now, these cooperative groups will come up with an idea for a clinical trial and that way, many centers all over the country can participate in these clinical trials. Allowing many people to help get outcomes that can ultimately move the field forward and it also means that patients all over the country can avail themselves of these trials. So you should look up clinicaltrials.gov. Look up cooperative groups and see what clinical trials patients might be eligible for in your institution. Multi-center trials are similar in the sense that they have many centers that are coalescing together to share data, to all participate in one clinical trial. These may not be cooperative groups in the sense that they may not be available to everybody, but only in those particular centers. Still, it allows us to collaborate to try to get these trials done in a fast and effective way. What about other kinds of trials? Not randomized control trials. We talk about cohort trials and case control trials. Cohort trials, as you can imagine, take a cohort or a group of patients. And then you can follow these patients and see which patients develop an outcome and which patients don't. So you take a group of patients and you say I'm going to follow these patients forward. Half of these patients smoke. Half of these patients don't smoke. We'll see who develops lung cancer. That gives you a sense. Case control trials are similar but almost backwards. So you have cases of patients who had breast cancer and controls who didn't get breast cancer. And then you go backwards and you see what are the ideologic factors that may have led to those outcomes? This brings us to the last set here, which is prospective studies, ones that go forward in time. These are often randomized control trials or cohort studies where we're following a group of patients over time versus retrospective studies. So studies where we go back in time, we look at data and we say, what caused this? What can we dig it out from the data that we already have historically, that may have led to these outcomes? Now, this is a key slide, especially for those of you who may be in this field and often are trying to remember all of the key trials that have really brought us to where we are in breast cancer management. It's funny because a lot of this seems like alphabet soup. Different trials with different letters and different numbers, trying to remember what all of these are. But these are really landmark trials, many of which we've talked about during this course. Remember the NSABP B-04 study? That was the study that randomized people to radical mastectomy where we removed the pectoral muscles and all of the lymph nodes to total mastectomy and the finding was that survival was the same. So, we really didn't need to take out muscles and all of the lymph nodes. Critical information as we moved forward because now, we don't do that. The NSABP-06 trial similarly was a landmark trial. This was the trial that randomized people to having a total mastectomy which remember with standard of care, just back in the 60s, to now breast conserving surgery. And the finding that these two were equal means that we can give patients these options. Remember back to the surgery section of this course? That was a critical element in what we talked about. What about the NSABP B-14 study? This was a study that looked at tamoxifen in estrogen receptive positive invasive cancer. Now this has become standard of care. B-18 was the neo-adjuvant chemotherapy study. Remember the study that had patients who were randomized to either receive chemotherapy followed by surgery? Or surgery followed by chemotherapy? Remember how that trial found that the survival rates were the same? So now we can offer patients either of these two strategies and we know the advantages and disadvantages of each. What about B-20? B-20 was the study that actually looked at chemotherapy, and showed that chemotherapy in breast cancer made a difference. B-24 started to look at DCIS, that pre-cancer, and the fact that tamoxifen could benefit patients, particularly now who have ER-positive DCIS, and that has become standard of care. What about B-32? B-32 was the trial that looked at sentinel node biopsy, and showed that really, survival was the same, whether you did a sentinel node biopsy followed by axillary node dissection only if the sentinel node was positive, or if you did an axillary node dissection on everybody. Revolutionized standard of care. The B-35 trial looked at aromatase inhibitors in DCIS. B-39 is looking at accelerated partial breast irradiation. B-42 was extended adjuvant therapy, so do you only need five years of hormonal therapy or is ten years really better? Some of these we're still waiting for the long-term results, more trials. MA-17, a great trial, looking at extended adjuvant therapy after tamoxifen. So this randomized patients who had had five years of tamoxifen to placebo versus an aromatasin inhibitor. Remember, placebo, because standard of care was only five years, and so they gave half the patients a placebo, half the patients an aromatase inhibitor after they had finished five years of tamoxifen. And this is another study that shows you the value of regulatory oversight, because this study was stopped early, why? Because the Data Safety and Monitoring Board, who is looking at this trial as it's going along, found while the study was going along that one arm was doing much better than the other arm. So they unblinded the trial, and what did they find? They found that the people in the aromatase inhibitor arm were doing better than the placebo arm. Remember, placebo was standard of care. And so, the patients who were on the trial, those were the first patients to find out the results of this study and it was opened up to the world so that everyone now knew, that extended adjuvant therapy had a benefit over five years of tamoxifen. Again, practice changing results from clinical trials. MA-20 was just recently reported showing the benefit of extended radiation fields. Z-11 has become practice changing even though it didn't find a statistically significant difference between the two arms. Remember, this was a non-inferiority trial, that means that instead of trying to find that one arm was better than the other, it was trying to find that two arms were equal, one arm of course was doing less, so would have less morbidity. Even though the Z-11 trial did not meet it's target accrual, sadly because too few surgeons put their patients on the trial, too few patients participated in the trial, it still became practice changing. Because we looked at the data and found, you know what, maybe we don't need to do an axillary node dissection even if patients have positive nodes. Again, clinical trials hugely important. The Zed-1071 trial looked at sentinel node biopsy after neoadjuvant chemotherapy. We had usually forced people to have a sentinel node biopsy before, that meant two operations, but this trial demonstrated that it was feasible to do a sentinel node biopsy after neoadjuvant chemotherapy. Prevention trials, the P-1 trial, showed that tamoxifen could reduce your risk of developing breast cancer by 50%. STAR trial found that raloxifene had an equal reduction of risk. We talked about these two when we looked at prevention. Go back and check it out if you haven't already. And then, newer trials are looking at Genomics. So the TAILORx trial, just one of the many trials looking at how we can use molecular biology to really tailor therapies. All of these, I hope, give you a flavor of how important these clinical trials are, how they really make a difference, and they're practice-changing. So I hope that all of you get as excited as I am about clinical trials. I really like this idea of patients and clinicians and researchers looking down that microscope of clinical trials together. Together, we are going to make treatment better and a brighter tomorrow. So until next time, I'm Dr. Anise Chagpar. Thanks so much for joining me.
