Speaker 1 00:05 Lange, welcome to HelixTalk, a podcast presented by the Rosalind Franklin University College of Pharmacy. Narrator - Dr. Abel 00:11 This podcast is produced by pharmacy faculty to supplement study material and provide relevant drug and professional topics. Speaker 1 00:19 We're hoping that our real life clinical pearls and discussions will help you stay up to date and improve your pharmacy knowledge. Narrator - Dr. Abel 00:27 This is an educational production copyright Rosalind Franklin University of Medicine and Science. Speaker 1 00:32 This podcast contains general information for educational purposes only. This is not professional advice and should not be used in lieu of obtaining advice from a qualified health care provider. Narrator - Dr. Abel 00:47 And now on to the show. Dr. Sean Kane 00:51 Welcome to Episode 15 of HelixTalk. I'm your co host, Dr. Kane. I'm Dr. Hartranft, and I'm Dr. shoeman, and we're missing Dr. Patel today, but today we're talking about cancer screening, and that's why we have Dr. Hartranft on the show today to discuss that she would be the content expert at the Speaker 2 01:08 university, and pleased to be here to participate. So why are you Dr. Sean Kane 01:12 passionate about this topic? What is it about cancer screening that you think is particularly relevant to patients, and probably commonly what you'll get questioned on by patients? Speaker 2 01:21 Well, it's something that every patient has, every patient sees. You know, not every patient is going to develop cancer in their lifetime. In fact, very few people really will, when we think about it in the global scheme of things, but many patients, all patients, really are eventually going to need to be screened for cancer. It's something we're all at risk for, even if we don't all develop it. And so I personally do get a lot of questions about what type of screening should I be getting? What's going to be the best test? When do I start? And I thought it would be a good idea for us to kind of talk about it, because everyone in the primary care setting is also going to be getting these questions, and it's good to know what the recommendations are and what the evidence is and why we make the recommendations that we do. And Dr. Kane, you and I were talking a little bit about the way that health care reform has been in the news lately. I think with the Affordable Care Act, a lot of people are suddenly afraid of terms like health care rationing. Have either of you heard patients kind of concerned about these type of issues, Speaker 3 02:17 not as much at a patient population, but certainly in the news, it is something to consider. They say, you know, when push comes to shove for dollars that we're making sure they're going to the more efficient ends. I think it's Speaker 2 02:28 absolutely something that I see in the news a lot people who are worried that we're going to stop screening for particular cancers, just because it's not economically feasible. Really, these recommendations come down to a patient outcomes perspective, and what's most safe and effective. And we can talk through some of the benefits and drawbacks to screening, but patients are very concerned about this. And also, I was recently reading an article one of the original researchers on the BRCA studies. BRCA being the breast cancer mutation gene that some patients have, it's linked a lot to familial breast cancer and to ovarian cancer, and sometimes even to prostate cancer, and I saw that she published an editorial in JAMA calling for universal screening of women for the presence of these mutations, regardless of family history. Now I don't see that as being incorporated into national guidelines anytime soon, because it's going to be outrageously expensive and there's such a small number of women who have these type of mutations that come to know and without a family history, but it's something that's on people's minds, I think, where we were planning to start with this. Dr. Sean Kane 03:31 So I from a patient point of view, I could absolutely understand why a patient would say, why would you not want to screen me for every cancer there is, as long as it's not an outrageous cost. Because, you know, if we catch cancers earlier, they're more treatable, they're less likely to become the disease that causes mortality in a patient if you're able to treat it earlier, Speaker 2 03:52 definitely, cancers that are caught earlier are much easier to treat than cancers that are caught later. And we see time and time again that the later stage you're at when you're diagnosed, the worse the prognosis for those patients. And that's a very frightening thing, but I think sometimes patients forget about the drawbacks that come along with this issue of more universal screening for cancers. And I Speaker 3 04:13 I know that when I think of a few of them, when I look at is the idea about false positives, we think about false negatives being detrimental. But with false positives, you can sometimes see anxiety as well as unnecessary additional testing and surgery. And I know in my patient population, when you give a diagnosis without a context, again, you have a lot of a lot of concern. So you really have to then do do a number of follow up tests or assessments, and then we also there's the identification of true cancers that would not have become clinically apparent, and so we have to consider what, you know, things that we're uncovering as we continue to look deeper. And I think we're going to hopefully talk further about some of the age cutoffs and life expectancy that we really do have to take into account and really be honest about those things in terms of our screening population. Speaker 2 04:56 Definitely, cancer is often called a disease of. The elderly, it's incidence certainly increases with age, and sometimes, if a patient isn't expected to live many years beyond really, why are we putting them through the stress and anxiety of screening and potentially the risks of treatment of a cancer that wouldn't have been harmful to them really in the first place? Dr. Sean Kane 05:16 So I would guess that some of the controversy, at least for breast and prostate cancer comes from the fact that we have dissenting guidelines, depending on who you ask, in terms of what is an appropriate screening tool or recommendation for different patient populations. So what are some of the organizations that are publishing guidelines for a variety of different cancers? Speaker 2 05:36 Well, Dr. King, you make a good point. There are numerous guidelines available. Unfortunately, we don't have one gold standard that we go to, which is frustrating sometimes for patients and physicians who want one single answer. But it's also nice, because we know we have multiple groups looking at the evidence and really delving in and trying to interpret it in the best way possible. But some of the major ones, and this is not an all inclusive list. Are the American Cancer Society, which is a community based group that's nationwide. They're headquartered in Atlanta. We also have the US Preventive Services Task Force that's a national organization created in 84 it's funded by the government, but it's independent in their recommendations, and most of the recommendations that they come up with are supported by the government, for example, are backed up by the CDC, the Centers for Disease Control, and they tend to be one of the more conservative guideline groups. When we're talking about oncology, we also have to talk about the NCCN, which is the National Comprehensive Cancer Network. This is a group that's made up of individuals from 25 of the nation's leading cancer hospitals, and they put out guidelines, not only on screening, but also on the treatment and follow up surveillance of cancers. And then finally, one of the other big oncology groups is ASCO, which is the American society of clinical oncology. It's been around since the 60s. And ASCO is really not a Guidelines Group. They're a professional organization. They represent physicians and oncologists who take care of cancer patients. So those are a few of the leading guideline producers. There are many more for several the disease states that we'll talk about. There are other smaller groups that also put out guidelines. And then, of course, every nation seems to have their own guidelines. So if we go over to Europe, we see NICE where we see the NHS in the UK. So there are many different guidelines that you can choose from, depending on what point of view you want to back up. Dr. Sean Kane 07:32 I think that really speaks to the gray area of medicine sometime, and I think sometimes students have trouble with that, and that there isn't always a black and white answer, and sometimes it's a very patient specific decision, as opposed to a population based decision. And I think having a number of guidelines that may disagree is sometimes a healthy thing. Speaker 3 07:51 And I think another point is that we'll probably touch on as we look at screening, is that not every cancer does have an appropriate screening regimen that we can do with for every case of a colorectal cancer which we can screen for, maybe have a glioblastoma or an osteosarcoma or some of these other very specialized cancers. And so we were kind of selected in what we can do Speaker 2 08:10 right groups are constantly researching and trying to find that magic bullet or that magic diagnostic test, but right now, we just don't have all that many and even as we'll discuss some of the screening guidelines that we have, or the diagnostic tools that we use, are far from perfect, and there's a lot of questions that remain about how best to apply them to cancer screening and cancer treatment. Dr. Sean Kane 08:31 So for the podcast today, we're going to be talking about a few of the less controversial screening recommendations, and then focusing on two of the more controversial screening recommendations. And you know, we are summarizing here, these are lengthy documents, in many cases, that describe a lot of the research behind it, and oftentimes they include patient specific risk factors that may alter the recommendations. So in someone with a history of colorectal cancer, as an example, they may have a more aggressive screening regimen, as opposed to someone with no family history. So we're trying to summarize trying to summarize as best we can for the purposes of the podcast, knowing that certain patients are going to have very specific recommendations. Speaker 3 09:10 So I think the first one we can start off with is looking at cervical cancer. And I believe this is one organ, one situation where we pretty much have an agreement between all the governing bodies, so the USPSTF, with the CDC, the American Cancer Society, and then also ACOG, the American College of Obstetricians and Gynecologists, all seem to be, you know, somewhat unanimous in stating, for example, that less than 21 years of age, we do not screen at all Speaker 2 09:35 correct patients shouldn't be starting on this until they're 21 regardless of their sexual history. And I think that's sometimes a misconception, that obstetricians or other physicians may think patients should start screening sooner, but we really don't screen until they're 21 years old. Dr. Sean Kane 09:50 So then once someone turns 21 between 21 and 29 years old, they should be getting the Pap smear cytology every three years, and they should not be tested for HPV or human papilloma virus at this point, and then things change when they hit age 30 Speaker 2 10:05 correct from ages 30 to 65 one of the recommended screening tools is co-testing, and that's doing both a pap smear and an HPV test every five years. Alternatively, patients can consider keeping up with the Pap smear alone every three years. Speaker 3 10:22 Then once we get above the age of 65 assuming that somebody has an adequate screening history and that they've been following up appropriate tests, then we can go ahead and stop that screening again unless we have other data patient specific that says that individual may be at risk for Dr. Sean Kane 10:36 cervical cancer. There's a few nuances to the cervical screening recommendations, depending on who you ask. So the USPSTF doesn't recommend co-testing as a preferred therapy for the age group of 30 to 65 but all of the other guidelines do. So. It's probably a reasonable recommendation for those that have had a hysterectomy, assuming that they didn't have that hysterectomy for cervical cancer, it's reasonable to not screen those individuals. And also any individual who's received the HPV vaccine, or the brand name is Gardasil, they should be screened just like everyone else. There's nothing special about them getting HPV that would preclude them from any specific testing that someone who did not get Gardasil should have. Speaker 2 11:17 And before we move on to the next cancer, I do want to mention that cervical cancer has really been one of the victories of cancer screening over the past few decades. Cervical cancer and other gynecologic cancers, on the whole, don't respond well to treatment, and so patients have very poor prognosis and can suffer a lot because of the radiation, surgery and chemotherapy that they have to endure. And so when we're able to prevent this by identifying abnormal cells on a pap smear and get rid of them before they can turn into a full blown cervical cancer, it's really quite something, and if you look at the rate of mortality from cervical cancer over the last few decades, it's really astounding, and it's a huge victory for the medical field in general. And ideally, we'd love to do that for every type of cancer, and we just haven't found that magic answer just yet. But cervical cancer, between the HPV vaccine, and even more so, from pap smear screening, has been a huge victory. I think Speaker 3 12:15 we're ready. We'll go ahead and start discussing the second one of these. We'll move on to colorectal cancer, and once again, this is one where we do have some common themes. Again, maybe not unanimous between them, we do have some common themes that state that we should go ahead and get a colonoscopy every 10 years. And then, with that, you know, any positive screen test would require a colonoscopy, if not already done. So there's a few other tests that can be done. They're really ultimately come down. You're going to still be doing a colonoscopy anyway, so that's a really important one to focus on every 10 years. Dr. Sean Kane 12:44 So a few alternatives that in my mind would be a little bit less preferred are the flexible sigmoidoscopy, which can be done every five years. And depending on the guideline you look at, they recommend on year three of your five years that you do something called a fit, a fecal immunochemical test or an FOBT, a fecal occult blood test, which is testing for blood in the stool. And that's at year three of five, depending on which guideline you look at, whether that is in conjunction or or not. Alternatively to both of those tests, you could do a fit or an FOBT every one year. But again, with any positive test, the follow up for that is a colonoscopy. So looking at the specific recommendations, there is kind of dissenting opinion. So if we start with the USPSTF, which again, is supported by the CDC, these were published in 2008 they're currently being updated. Currently. They say if you're between the ages of 50 to 75 you should be screened using your screening tool of choice that you should not screen adults 76 to 85 years of age unless there's a compelling reason, so they've had some family history or other risk factor. Then the USPSTF says that if you're above 85 years of age, that you should not be screened for colon cancer at all, again, if there's some compelling reason, okay, but for the general population, no screening should be used for the adults greater than 85 Speaker 3 14:07 and then, I think a little bit different. Well, starting out the same as the American Cancer Society says to start your screen at age 50, as does the USPSTF, but in in this case, they actually stated there's no upper age one, so they continue to do those screenings again, essentially indefinitely, without putting a cap on it based upon age. And then I think what's interesting too, is that there are a couple other screening options here that aren't really discussed by the other guidelines. And one of those options would be the double contrast barium enema. Sounds wonderful, but every five years, as well as a CT colonography or virtual colonoscopy. And again, that can be done every five years as an alternative. Speaker 2 14:43 And I think it's interesting you point out that there's no upper age limit specified by the NCCN or the ACS. And I think again, we see a good example of the fact that the US Preventive Services Task Force tends to be the more conservative guideline and try and limit the amount of testing where. Is the other physician oriented groups really try and promote the issue of individualized patient by patient decision making, and do a good job in their guidelines of promoting discussion between provider and patient and making an individual decision rather than adhering to a national or global guideline. Dr. Sean Kane 15:19 So Dr. Hartranft, what would be the best argument against basically having no age restriction or no upper limit of age? What would the uspsts say in terms of why they picked 85 as their cut off for a reasonable recommendation to stop screening? Speaker 2 15:37 Well, I think when you consider your typical 85 year old patient, and we think about the fact that colonoscopies are only given every 10 years as a screening tool. If you have a patient who's 85 years old, or let's say they were 84 they were still eligible for colonoscopy. They had one in 10 years they're 94 years old. Would you really want to do a colonoscopy on a 94 year old given the risks of an invasive procedure like that, and also their life expectancy. So I think it's a fair argument by the US Preventive Services Task Force Against screening in the elderly population, you might hear arguments from physicians that there are some 84- or 94-year-olds who are extremely fit, who they could easily see living another 10 years. And that's where your clinical decision making really comes into play. Dr. Sean Kane 16:28 I think kind of piggybacking on that. The other issue is, what do you do when you have a positive colonoscopy test as a screening tool? Are you going to give that 94 year old, you know, surgery, chemotherapy, any other treatment, is that really, you know what would be down the road for that patient? So moving on to the third, less controversial type of cancer screening, lung cancer and Dr. Harran, as I understand it, a new, newer study came out that kind of solidified some of the recommendations regarding this. That was the nlst trial, right? Speaker 2 17:01 The ball game really changed in lung cancer screening back in 2012 with the publication of results from the National Lung Screening Trial the nlst. Prior to that, there wasn't really routine screening done. There were no standardized guidelines. Some physicians were referring their patients who seemed to be at high risk, so had environmental exposure or a history of smoking, these patients may be referred to for a CT scan or for a chest X ray, but there wasn't always good evidence for routine screening among this population. Now, based on the evidence from this trial, we can definitely recommend a screening with a low dose CT scan yearly for patients at high risk. And so those based on the evidence from the trial, are patients who are 55 to 74 years old. So again, we see an age range. We want patients to be old enough to be at high risk for developing cancer, but not old enough that their life expectancy is such that the risks of screening and treatment wouldn't be disabling. So patients have to be at least 55 to 74 and have the following conditions, a pack year history of at least 30 and have either be a current smoker or have quit within the last 15 years. If they quit at least 15 years ago, their risk for lung cancer has dropped sufficiently that they are not eligible for screening. And of course, patients have to be in relatively good health, we're not going to screen someone who is going to die of a heart attack next year. Anyhow, the other issue is we can screen patients who are a little bit older. Again, guidelines sort of differ. The American College of Chest Physicians, the American Lung Association and the American Cancer Society capped their screening recommendations at 74 but the US Preventive Services Task Force, interestingly enough, caps theirs at age 80. Dr. Sean Kane 18:51 That's kind of the opposite theme that we usually see from the Preventive Services Task Force, right? Speaker 2 18:57 It is. And I was a little bit surprised to see that they had done that, but they looked at the evidence, and that was the conclusion that they drew. Dr. Sean Kane 19:03 As I understand it, there's kind of a moderate risk group that you could also consider screening. This is from the NCCN and the American Association of thoracic surgery. This is someone 50 years or older with a 20 pack year history plus a risk factor. So again, 30 pack year history is kind of what qualifies you. In this case, it's 20 pack your history plus another risk factor. And there's a laundry list of different risk factors that are out there. Speaker 2 19:27 There are and some of them, some of the big risk factors may include exposure to second hand smoke over a number of years, environmental exposures like radon or asbestos. But as always, we would recommend going straight to the guidelines if you have any question about whether a patient is eligible for screening or not. Dr. Sean Kane 19:45 So moving on to two of the most controversial screening areas, the first being breast cancer screening. And really the three screening methodologies that we have is a clinical breast exam, self breast exam. And then probably the most commonly heard of is a mammography, right? Speaker 2 20:04 And breast cancer screening generates a lot of very heated debate. I'm sure we've all seen it in the news before. I wanted to take a step back and talk about some of the basics. So a clinical breast exam, as you mentioned, is one of our modalities, and that's when women are in to see their physician or their obstetrician and get a breast exam from that health provider who's trained to know what to look for when it comes to various lumps and bumps. A self breast exam, sometimes called breast awareness, is when women do their own self breast exam, and the recommendations on this actually vary in the US. It's very common for women to do a monthly self breast exam in Europe and the UK, it's less common those recommendations aren't as strongly enforced, nor are they really as strongly recommended at all. And then, of course, as you mentioned, the most contentious, which is mammograms. And mammograms really made the news a few years ago, when the US Preventive Services Task Force changed their recommendations from mammograms starting at age 40 and moved that age up to 50 and changed from yearly mammograms to every other year mammograms. And this is where that issue of rationing care came up, as many women thought that they were having their opportunity to have breast cancers found early taken away from them. And there were a lot of women who went up to Capitol Hill with stories of early detection because of annual mammograms. So we wanted to take an opportunity to go through some of the evidence, I think, and Dr. Sean Kane 21:34 to clarify was that coincidence that those two things happened at the same time as the discussion about Obamacare healthcare was going about, or were they interrelated? Where the decision was made, in conjunction with some of the changes with healthcare? Speaker 2 21:49 As far as I'm aware, they were two separate changes. I think that those recommendations had been under review for quite some time, and certainly these guidelines, as we talked about early on in the podcast are not based on economic considerations. They're really based on the scientific evidence and the best outcomes for patients, and trying to avoid over diagnosis and over treatment and detection of false positives that end up causing harm to women while still trying to find the vast majority of aggressive cancers that are going to be dangerous to the women are in our population. Dr. Sean Kane 22:23 So Dr. Shubin, what are some of the risks and benefits of a mammogram in the first place? Oh, right off the Speaker 3 22:29 bat, what a mammogram is. It's similar to an x ray. It's actually just an x ray of the breast tissue. And one of the main benefits is kind of obviously, is that it may detect breast cancer before it can be palpable. So before you get to the point where you pick it up on that self exam, before you go into a clinic appointment and have it palpated, you may be able to pick up that mass on the X ray. So, again, on its face, very, very reasonable idea. But then there are some some drawbacks or limitations with and I think the first one, going back to false positives, is going to be that you can have some of the additional diagnostic investigation required, and it can be pretty invasive going on and doing a biopsy, and then you may find that those abnormalities are not cancerous at all. It could be some sort of another mask that pops up. So you've gone to not just in terms of healthcare dollars, but the stress and the fear you place on this individual to get them to that point, to just say, Okay, well, actually it was non cancerous. And there can be some limitations there. And I think another one on that same page is going to be over diagnosis or over treatment, whether there's even a ductal cancer that may be picked up there, and it can be either in situ or a slow growing breast cancer also. And these things may not pose a threat to the patient, but once again, they're going to be picked up, seen on the exam, identified and treated, and there may be some risk associated with that treatment as well. And again, you know, what is the benefit there for the individual versus the risk of harm? Right? Speaker 2 23:50 And with all these potential drawbacks to mammograms, a lot of women are finding themselves asking, Well, why aren't we doing something else? And there's been other modalities tried, like three dimensional mammograms, like MRIs, but right now, they haven't been studied in enough women to be able to validate whether these are effective screening tools or not. What we have is the two view mammogram that's been in use for many decades and has been shown to detect a lot of aggressive breast cancers and a lot of malignant tumors that are going to be problems for our patients. And so I can't, as a oncology healthcare professional right now, say to patients that an MRI or three dimensional mammogram is better, because right now the evidence is with the two dimensional mammograms. But I'm really looking forward to seeing what some of the ongoing research suggests for the future, Dr. Sean Kane 24:38 and in thinking about the evidence, you know, one of the reasons that we don't have firm answers is that we have either conflicting data or data that can be interpreted a variety of different ways. So I would assume with breast cancer screening, there must be some trial that says that we should do X or Y, and there must be a different way to interpret Speaker 2 24:56 that trial. Well, wouldn't you know we have multiple trials? Conflicting evidence, and I brought two today that I want to talk about. The first was published just earlier this year, and that's results from the Canadian National Breast Screening study. The original results from this study were published back in 1992 but they've just come out with the 25 year results very quickly. This was a study with about 90,000 women at 15 centers across Canada. They ranged in age between 40 to 59 and they were split into two groups based on age. So there was a group between 40 and 49 and a group between 50 and 59 this most recent publication, they lumped all the data together and found that there really was no difference between the arms, regardless of which age group you looked at. Basically what they did was they randomized women to five annual mammograms or to a control group, which was just usual practice. So for all we know is these women had annual mammograms for five years after that, that they may or may not have had other mammograms done, but this design was really just to look at what happened in that five years, and then they followed up on it. Dr. Sean Kane 26:06 You know, going back to the study design and inclusion criteria, these are women, not at 50 years, but at 40 years, who had an annual mammogram, as opposed to every other year, which, as you mentioned earlier, was a change in some of the guidelines correct. Speaker 2 26:21 And so this is a very young group of women. They were trying to catch cancers quite early. The other thing that's interesting is that the study was begun in 1980 and so really, the treatment modalities that we had at that time were vastly different than what we have now. We didn't have the same type of hormonal treatments back in the 80s that we do now. And so we can't really make a lot of conclusions necessarily about some of the outcomes in this study just because of how drastically treatment algorithms have changed. Dr. Sean Kane 26:50 So what were the findings of the study in terms of how, how good were they at finding these breast cancers, and how often did patients die of breast cancer? Speaker 2 26:58 Well, as for results, they were really good at finding breast cancers. If you look at this study arm, the group that had the mammographies every year for five years, they found 666 cancers on screening in the mammogram arm versus the control arm, where they only found 524 cancers in evenly split groups. However, overall, they didn't find any difference in survival. So while they may have found and treated more cancers, they didn't actually save any lives when you drill down into the data. So what's happening? At least, what the authors suggest is that they're identifying cancers that wouldn't have been fatal to their patients in the long run, anyhow, and really, we just over diagnosed and then subsequently over treated these women. Dr. Sean Kane 27:51 So this might be a difficult concept for a pharmacy student as an example. So you're saying that these patients had breast cancer that did not benefit from treatment, because they would have died from some other reason. Correct? Speaker 2 28:04 It looks like really in their estimation. What the authors suggest is that among the 90,000 women that they screened, they found 106 cancers in the mammography arm that they would not have identified in those same patients had they been in the control group and those cancers, those extra 106 were over diagnosed, that these were cancers which were slow growing and so non aggressive that the patient would have been just fine if they had never been discovered, and the patient had never had to go through treatment. This does seem a little bit surprising and probably hard for us to wrap our minds around. How can it be that finding a cancer is not a good thing, right? If we've found a cancer, we can treat it, we can combat it. But the issue is that, as I said, those cancers might be slow growing. The other problem is that treatment carries its own risks, so we don't know really if the fact that we treated these women caused them to have problems, caused them additional morbidity and mortality, especially when we go back to thinking about the breast cancer treatments that we used in the 80s and 90s, it was extremely aggressive. There was a while during the 90s that women who had breast cancer, depending on how aggressive it was and what stage they were diagnosed at, they actually may have gone for an autologous bone marrow transplant to rescue them from the effects of their chemotherapy. That's a really tough regimen to tolerate, and so we're exposing women to all these additional risks that they may not have been exposed to had we never even screened them in the first place. Dr. Sean Kane 29:42 So overall, it seems like this is a relatively negative study against the practice of doing a yearly mammogram in the 40 plus year old type of patient. Exactly. Speaker 2 29:53 I mean, I don't think that we can necessarily say mammograms are useless based on this one study, but it certainly didn't show. An overall survival benefit, at least in this younger population. Dr. Sean Kane 30:05 Perhaps this is the evidence based pharmacist in me. But I love the fact that we have really a dissenting difference in outcome of the trial, and it really matters. When looking at a trial, you know, what endpoint Are you really interested in? Most people when they think of, well, if you're screening for breast cancer, the endpoint should be whether you found more breast cancers or not, but in this case, with a mortality endpoint, it really changes the interpretation of the benefit of the treatment on the trial. Speaker 3 30:32 And I think I know when I look at one other potential critique of the study too, I believe, is that it seems that they may have had a lower than expected rate of that breast cancer that was identified by the mammograms, and that may be an issue with the technicians or radiologists who are doing the exams. Could you comment on that a little Speaker 2 30:47 bit more? Right? That's been a critique of the study all along. Interestingly, when they published the first data back in the 90s, this showed up right away that they were only getting about a 1.5% rate of breast cancer finding in their patients, and it maybe should have been higher based on overall epidemiologic trends at the time. So that kind of called into question the expertise of the radiologists and the technicians. However, part of the problem was that these were one dimensional mammograms. We now do two view mammograms, so we have a little bit better mammogram technique nowadays. The other issue is that it was kind of a training problem, and the researchers identified that very on and you see rates go up from the first year of the study through the end of the study. But it is a problem to consider how many breast cancers may have been missed in the mammogram group that would have contributed to possibly a better outcome for that active study group. Dr. Sean Kane 31:47 So given the controversy and the relatively negative findings of this study, there must be a very positive study in support of more aggressive mammogram screening. Speaker 2 31:58 I think you must be referring to the Swedish two county study. This is another trial that was conducted about the same time. It was started just a few years before the Canadian study. This one was started back in 1977 so again, we have the same type of issues with the one view versus two view mammograms, the changes in treatment algorithms for breast cancer patients since then, but this one shows quite different results than the Canadian arm, in that this is one of the reasons that we are still doing mammograms. The latest results of this study, which is being assessed, as I said, since 1977 the 29 year results were published in the Journal of radiology back in 2011 this study is a little bit larger. It was 133,000 women, and I had a broader age group. So again, women from age 40 were invited, but there was no age cap, so it's actually enrolled patients between 40 and 74 these were women from two Swedish counties. So I think one critique of the study is the issue of patient selection. But either way, we still have 133,000 women to look at. What's interesting about the design of this study is the way that they did the mammograms. So in the Canadian study, we have one group that had yearly mammograms and the other that did not have any mammograms, we had 90% compliance in that study with both groups. The Swedish study had different recommendations based on patient's age, so the younger patients, those age 40 to 49 were screened every two years with mammograms, and when I see screened, they were actually invited to participate. It wasn't any kind of requirement. They just received an invitation in the mail. But they did have about 85% participation. The older patients, those aged 50 to 74 were screened at a mean of every 33 months. So close to three years, we have slightly higher rates of breast cancer diagnoses overall in these groups, 1.8 to 1.9% of patients who were eventually diagnosed with breast cancer, and overall, when they looked at the data from the 29 year study, they found that cumulative mortality was significantly reduced in the active study population with a hazard ratio of point six nine. And so their conclusion was that screening for breast cancer with mammograms significantly reduced this mortality, which was not what the Canadian study had shown. And so this is why we still see mammograms as one of our most important screening modalities for this disease state. Speaker 3 34:44 So Doctor Kane, it sounds like a pretty big slam dunk. And in favor of mammograms, you see anything in here that maybe anything we can look at as our, you know, take this study apart a Dr. Sean Kane 34:54 little bit. So I think one of my biggest critiques of the study would be looking at, certainly we have a positive. Of result in the sense of a significant P value with that hazard ratio, 0.69 but I think it's also important to look at the clinical relevance of the difference. So with the active participation group, the diagnosis rate was 1.8 versus 1.9% with the control group, and if you actually look at breast cancer mortality, the difference was 0.45% versus 0.6% so if we were to calculate a number needed to treat, for example, that would be a very, very large number, because the incidence rate is so small, meaning that you have to screen a lot of different women in order to catch one breast cancer, in order to prevent one mortality from breast cancer, Speaker 2 35:39 I think you would find that patients who have been through cancer themselves or who have a friend or family member who had cancer would say to you, Dr. Kane, Isn't it worth it, though, to screen 1000 patients to be able to save that one patient from cancer? Yeah. Dr. Sean Kane 35:53 And it really goes back to the issue of false positive rates and things like that, in terms of what is the benefit versus risk, and that's exactly the reason why this is such a controversial topic. Speaker 2 36:05 Well, it seems that the evidence is still out, and we're going to have to wait for more studies and more meta analyzes to really be able to come to a conclusive decision on what's absolutely best. But when you have patients ask you what the guidelines are, what is your answer for them? Dr. Sean Kane 36:22 So if we look at the US Preventive Services Task Force, these were published in 2009 supported by the CDC, and they are very interested in keeping these as up to date as possible, as new evidence comes in. But their recommendation is, if you're in your 40s and you're female, that it should be a case by case basis for mammography screening as you reach 50 years of age, up until 74 years of age, it's every two years of screening. And they do say that, you know, we do see a mortality benefit with screening in this age group, which was based on the trial we just discussed, for women greater than 75 years of age, they essentially have no recommendation. They say that there's insufficient evidence in terms of weighing the risk versus the benefit with the knowledge that there is a risk that over diagnosis in this patient population is a concern. They do recommend, and this is interesting, against teaching patients breast self exam. And the reason is that they cite two different trials that showed no mortality benefit among patients who were taught to conduct a self breast exam, and then they say that there's insufficient evidence for a clinical breast exam in women greater than 40 years of age. Again, they cite a study showing no mortality benefit and recommend the mammogram in this patient population as they get about 50 years of age. Speaker 3 37:44 And I think this is where we start to see a little bit of that controversy come forth. Because then we will we look at the American Cancer Society. As long as a woman is considered in good health, they can go ahead and they recommend doing a yearly mammogram at starting at year 40. So again, these are going to be a little less conservative than those put forth by the USPSTF. And then so you have yearly nanograms 40 and up. And actually they recommend a clinical breast exam from anyone between 20 and 39 to do them. We limit them to every three years. But again, whereas it's not even recommended at all in the USPSTF here, every three years, and then women 40 and up to actually do it every single year. And then they continue to espouse for the breast self exam, it's not quite mandated, but something that's optional for any woman from 20 years old and up, so definitely flies in the face of some of the more conservative USPSTF recommendations. Speaker 2 38:38 And I think you'll find that the NCCN guidelines really mirror the American Cancer Society guidelines in that they recommend clinical breast exams every one to three years and breast awareness so that that is a breast self exam for women ages 25 to 39 so they wait until a little bit older, and Then they also recommend an annual mammogram and clinical exam for women who are at age 40 or greater. So the old recommendations that the USPSTF used to enforce, but has since changed ASCO, the American Society of Clinical Oncology, does not have a guideline on this particular disease state. But interestingly, when the new US guidelines came out, ASCO weighed in and put out a position paper in response to that, and again, in response to the publication earlier this year with the results of the Canadian National Breast Screening updates suggesting that all women speak with their doctors about their personal risk for breast cancer starting at age 40, and that the organization felt there should be no overall change to the guideline recommendations. So again, we see another large cancer group suggesting that yearly mammograms starting at age 40 would be recommended, or at least that these decisions should be made on a case. By case basis. Dr. Sean Kane 40:01 So Dr. Hartree, I would imagine that the recommendation, given the controversy, is really going to depend on things like patient specific risk factors, family history, anything along those lines. But let's say for a run of the mill, no family history. 41 year old female. Should she, in your opinion, be getting a mammogram. Should she be doing a clinical breast exam or a self breast exam? Where do you kind of weigh in with these dissenting guidelines? Speaker 2 40:29 Well, obviously, every patient has the right to the information that's available, and I would certainly recommend that they make an informed decision themselves with the available evidence. Personally, I would suggest that for a woman with no other risk factors, so no family history, no other significant risk factors for breast cancer, that I would suggest that they hold off, or if they are going to screen, that they do it every two years, as we saw that even every two year, mammograms in the Swedish study were beneficial in terms of overall mortality, I do see quite a few patients who end up being referred for more diagnostic evaluation who don't have cancer, and it's a very troubling thing for a woman to have to go through, to have additional diagnostic mammograms done, to have a biopsy done, to go through that fear and worry just to find out that it was nothing to begin with, or alternatively, to find out that she does have cancer, but that it's not likely to be a problem. So it's something like a ductal carcinoma in situ that many women have, and it puts them at risk for additional breast cancer, for transformation of those cells into a true malignancy. But what do you do with that information? Do you go ahead and treat now, knowing that there may not necessarily be an overall benefit just because you want to get rid of those cells? So these are big questions that every woman needs to grapple with. And I think as we see more and more evidence come out, and we see more celebrities like Angelina Jolie come out with their personal decisions. We're all going to be encountering these type of questions on a regular basis. Speaker 4 42:06 And what was Angelina Jolie's personal decision? Speaker 2 42:10 So Angelina Jolie did not have cancer, but she has a family history of breast and ovarian cancer, and she screened positive for the BRCA mutation, which put her at a very high risk of developing either one of those cancers. So she made the decision to go ahead and have a double mastectomy and have both of her breasts removed so that those would not pose a danger to her in terms of developing cancer in the future. And I really admire her decision. That's a hard decision for anyone to have to make. However, every patient has to weigh for themselves how much it's worth to them to go into the knife and have that done. Knowing that just because you have a mutation does not necessarily mean that you will develop cancer. Dr. Sean Kane 42:56 So while that's very interesting, I think it's time to turn the tables a little bit, and Dr. Schuman and I may be able to weigh in a little bit more on the other controversial area, which is prostate cancer screening using what's called PSA, which is prostate specific antigen. Speaker 3 43:12 Alright, so just to kind of kick it off and talk about what the PSA is, again, prostate specific antigen, or PSA, in the chart, it's a glycoprotein. It's secreted by the prostatic epithelial cells. So the cells in the prostate can be elevated. They'll do a lot of different things. We can think of it again in terms of prostate cancer, but also infection, recent instrumentation, ejaculation or trauma, all these things can elevate your PSA for additional reasons. Dr. Sean Kane 43:39 You know, initially, PSA was approved to monitor the progression of patients who had prostate cancer, as opposed to a screening tool. And that was approved in 1986 in 1994 it was approved as a screening test in conjunction with a digital rectal exam for prostate cancer. Speaker 3 43:58 And I think once again, the concern with it is that there may not be, or doesn't appear to be, at this time, what's considered a normal or abnormal level in the blood, since we do have fluctuations in the past, so that a level of four nanograms per milliliter, and then lower than anything lower than that, was considered normal, but it started to fall in a favor, because there can be some high variation of PSA levels among men. I know, for example, we talked about, if you start somebody on certain medications, such as finasteride for their the name prostatic hyperplasia or BPH, then you can see, you know, maybe a change in their PSA there. So there can be a lot of things can that can affect it and and so now we've kind of taken away from saying there's a set level, Dr. Sean Kane 44:37 and just like breast cancer, there's risks to screening and having false positives, so over treatment. So if a patient has prostate cancer, and had they not received treatment, they would have died from something different anyway. Did you really do benefit by giving them treatment for their prostate cancer, especially given some of the complications of the treatment for prostate cancer, specifically things like erectile. Function and urinary incontinence. And I think it Speaker 3 45:02 comes, yeah, it comes down to why that we have to have an honest discussion about quality of life issues, and really, again, give it, you know, to the patient, in both the pros and the cons of doing these, you know, early assessments as well as the responses to it. What that can mean that, in terms of just the short term addressing, you know, the cancer or risk of cancer, but what even you know again, once it's if it's been successfully treated, or we've treated what we think is a cancer, you know what that's going to look like in terms of some of the complications, and just be honest about it. Dr. Sean Kane 45:29 So, Dr. Hart ramps, I know that you have something to feed. My hunger for evidence based medicine with prostate screening. Speaker 2 45:37 Well, I did not come empty handed. I brought for you guys an article that was published in the Journal of the American Medical Association back in March of this year. That was a review article that focused mainly on two of the biggest studies when it comes to using PSA for prostate cancer screening. These are the prostate, lung, colorectal and ovarian Screening Trial the PLCO and the European randomized study of screening for prostate cancer, the erspc, and just like the breast cancer studies that we talked about, these two have conflicting results. Awesome. It's always good for us to have something to chat about. So the PLCO study enrolled close to 80,000 men between the ages of 55 and 74 they were randomized to either receive an annual PSA for six years, plus a digital rectal exam for the first four years, or to usual care, which may have included PSA and Dre but that information was not collected The 13 year data shows that the prostate cancer incidence was similar in both groups, with 11% in the screening group and 10% in the control group, which we would expect it to be slightly higher in the group that we're actively looking for cancer in. However, despite the fact that out of these patients, over 10% had cancer, the mortality was only point 4% in both groups. There was no statistically significant difference in mortality between the screening group and the control group. In the PLCO trial, in the erspc trial, we found that 182,000 men in seven different countries were randomized to be screened with a PSA without a digital rectal exam every four years. So this is somewhat unusual. Most PSA screening we see is annual. This group only was screened every four years. The one exception was patients enrolled in Sweden, received their screening every two years, and then there was a control group that didn't have any standard screening. Prostate cancer incidence in this group was similar 10% in the screening group and then lower down to 6% in the control group, as I say, expected, the mortality here was similar to what we saw in the last group, but it was statistically significantly different between the two groups, with a benefit in favor of screening among the 10% of patients who were found to have prostate cancer, point 4% of the overall group ended up dying of their prostate cancer among the control group where 6% eventually were diagnosed with prostate cancer, point 5% of the men in that entire study arm eventually died from their cancer. This was statistically significant. This point 4% mortality versus point 5% mortality. Dr. Sean Kane 48:40 I just want to contrast this with the breast cancer screening trials that we looked at. So we have anywhere from six to 10% incidence of prostate cancer here among what would be considered a high risk group of prostate cancer in the breast cancer trial, what did we see for reasonable incidents among those patients that were Speaker 2 48:59 screened among the studies that we reviewed, incidence was about 1.5% so we see just a small fraction of the numbers that we see here for prostate cancer. Dr. Sean Kane 49:08 So prostate cancer much more common among this green population, despite the fact that prostate cancer was much more common than breast cancer in these two different trials, the risk of dying from prostate cancer, especially given that the incidence was so high, was really not that compelling compared to the risk of breast cancer mortality. And those trials, we saw patients who did have breast cancer had fairly high mortality rates. Speaker 2 49:34 It's true, about a quarter of the patients in the breast cancer studies eventually passed away from their disease, whereas here we see maybe 4% of patients passing away from their cancer, so a much smaller number. Dr. Sean Kane 49:48 I would imagine that incidence rates and mortality rates kind of jive with what you currently see in clinical practice, where prostate cancer is more common, less deadly, and the reverse is true with breast cancer. Is that correct? Absolutely? Speaker 2 50:00 Definitely mirrors what I see in clinical practice every day. Speaker 3 50:02 And again, like any good study, there's going to be things that we can pick apart about about these still. Anyway, so the PLCO trial, one of the things that individuals have noticed and commented on, in on it is the low proportion of black males as well as males with a family history of prostate cancer, again, conveying some of that high risk population. Also noticed a low rate of biopsies. Interestingly, among men with suspicious results, actually less than 50% then had a biopsy, and there was also seemed to be some contamination of the control group with PSA testing about 50% annually in the sixth year of screening. Speaker 2 50:35 Right among both studies, the control group was randomized to standard care, and depending on the opinions of your treating physician. Standard care may or may not include a digital rectal exam or a PSA screen. Dr. Sean Kane 50:47 So then the argument is that there was almost too much crossover to see the true effect of doing PSA screening with some given interval, as opposed to not doing it at all, which is perhaps not what the studies were examining Exactly. Speaker 3 51:01 Another interesting in the in the ers PC study, the interval the PSA screening was somewhat interesting, the idea that it was done every four years in six of the seven countries. But then in the one cut in Sweden in particular, done every two years. It's because of some of that these discordant results there maybe have to consider the applicability between the United States population. Speaker 2 51:22 Of course, in the US, when we screen, we seem to enjoy over screening and doing annual PSA tests for men who are going to get their PSA tested. And so it's really interesting to note that this study that showed a benefit to PSA screening, they really only screened every four years, or at most, every two years. And this really mirrors what we saw with the breast cancer group, and that screening with a mammography every two years was sufficient for a mortality benefit. And here we see that screening for PSA every two to four years may confer a mortality benefit. Speaker 3 51:55 And I think one last thing to see is kind of as we compare and contrast the two is since the nature of prostate cancer being a slow growing cancer is we have to look at the length of follow up is 10 to 13 years, maybe enough time to see these benefits and harm in something that is going to be so slow growing over time. Dr. Sean Kane 52:13 So I'm kind of summarizing some of the data, thinking about what are some of the recommendations from these two trials that we looked at. We're definitely focusing on men aged 55 to 69 in these trials, maybe PSA every other year, maybe a little bit more frequently in those with risk factors, maybe a little bit less frequently every three to four years, if the PSA is very low, so less than one and you know, even thinking about when to biopsy. You know, one of the studies, they were biopsying less than 50% of the time when they had an elevated PSA. So maybe a biopsy is not always the next step when the PSA is elevated, perhaps watchful waiting or surveillance would be more appropriate than an invasive biopsy or even treatment of potential prostate cancer. So given the controversy, I'm sure that we have plenty of controversial guidelines that go along with the controversial studies that are out there, Speaker 2 53:02 we certainly do, just like with breast cancer, every group seems to take their own approach to interpretation of this data, and as we've already talked about, the United States Preventive Services Task Force is one of the more conservative groups. So when we go ahead and look at their recommendations, they're really quite staunchly against the use of PSA in testing for prostate cancer. They recommend its use in following patients who have already been diagnosed, but they really don't encourage its use as a screening tool, and they have some numbers to back them up. If you go on their website, you'll see a really nice infographic, but basically they put out the case of, let's say we screen 1000 men for prostate cancer using PSA. If we screen 1000 men, we will save one life. However, 30 to 40 men will end up with urinary incontinence or erectile dysfunction due to treatment for their prostate cancer. Two will have a serious cardiovascular event due to treatment for their prostate cancer. One will have a DVT or PE due to treatment for prostate cancer. And if we expand this case to 3000 men, one in 3000 will actually die due to complications from surgery for prostate cancer. So there's some interesting numbers. Whether it's valid for the US pstf to be so strongly against PSA, I think we'll leave it for our listeners to decide, but that's the opinion that they have taken. Dr. Sean Kane 54:37 And again, I think it's so neat that on their website, they've really used what is a number needed to treat more number needed to harm, to communicate risk and benefit to a patient population, which I think is fantastic for communication with the patient, to describe the actual risk and benefit, as opposed to giving them 0.4 versus 0.5% I think that it's an ultra. Way to describe the data that may be more intuitive for patients to understand Speaker 2 55:04 right hard to discuss hazard ratios with patients, but showing them a chart or a graph or other visual aid is very helpful. Dr. Sean Kane 55:12 So kind of moving on to some of the other recommendations. The ASCO guidelines published in 2012 basically say that if your life expectancy is greater than 10 years, that you should talk to your doctor. So they kind of provide a soft recommendation, of it's a patient specific decision, as opposed to the Preventive Services Task Force that kind of didn't even provide that language. They said, just don't do it, which I think is a pretty strong recommendation when you think Speaker 3 55:38 about it. All right, then I think the one of the last ones we'll talk about is going to be the American Cancer Society, and see if maybe they can mitigate some sort of a middle ground between the other factions at war here. So what they've stated is that the research is somewhat inconclusive about, again, the risks and the benefits. And what Dr. Kanepointed out with the USPSTF, again, maybe too against it, but giving out some good numbers, the ACS has stated that, again, risk benefits, a little bit inconclusive. So what, what they've decided is that those above 50 years old, we can discuss with the MD, and once again, make an informed decision looking at some of those numbers we have about this is the odds of it occurring. This is what would happen if we treated it. You know, this is the benefit you can see, as well as these are, this is some of the fallout, and they've also really tried to look at those risk groups, and I think that's an important thing to look out of that data, is who really is at risk, and what they've stated and kind of stratified, is those greater than 50 years of age, especially African Americans, those either with a father, a brother or a son that had prostate cancer at an early age, could actually, excuse me, with those groups, we can actually decrease down to 45 years of age, consider and consider high risk, and then maybe we even start the screening a little bit earlier in somebody that has the highest risk, and that would be an individual with more than one first degree relative who did specifically have prostate cancer at a very an early age. And then, once again, they've said, you know, if the PSA test is done, the frequency of the subsequent test needs to be based upon the PSA level. So if it's if it's low, if it seems appropriate, then we don't have to continue to do that every single year. Keep checking Speaker 2 57:13 the last prostate cancer screening guideline I want to mention is the NCCN, and as we've seen time and time again, they tend to be one of the more aggressive proponents of screening. And so the NCCN actually lays out particular thresholds for testing of the PSA, which is very interesting. They're the only group I think that still does this. So to summarize the NCCN recommendations, we see that for men age 45 to 49 they do recommend both the digital rectal exam and a PSA check if the digital rectal exam is abnormal at all. They recommend further testing if the digital rectal exam is normal and the PSA is normal. Patients can hold off testing for five years, just wait until they're 50. However, if the digital rectal exam is normal, but the PSA is greater than one, they recommend rechecking in one to two years. So their threshold, really, for these younger patients, is a PSA of one nanogram per mil. That would be high to them, and they would encourage more regular checking after that. For patients who are 50 to 70, again, they recommend both a digital rectal exam and a PSA. However, their threshold goes up as age increases. So for men who are age 50 to 70, a normal PSA. According to the NCCN, is three. If it's less than three, you can repeat testing every one to two years. If it's greater than three, they will recommend possible referral for additional follow up or diagnostic testing in men who are greater than age 70, the NCCN recommends only testing and those men who are relatively healthy have few comorbidities and are expected to have a relatively long lifespan in the future. For those who are in poor health or who are not expected to live for many more years. They don't really make any strong recommendation, but the implication is that they would not recommend PSA testing in that group. Dr. Sean Kane 59:11 So just to kind of summarize, we have one group that's saying, do not do PSA testing period. We have another group that says, talk to your doctor once you turn 50, maybe a little bit lower age, cut off if you have risk factors, and then we have another group that basically says, be doing a Dre and a PSA. Essentially, once you turn 45 years of age, those are about as discordant as you could be in terms of recommendations. So I can completely understand the confusion that a patient would have knowing that it completely depends on the physician or the guideline that that physician follows in terms of what is a reasonable screening procedure. I think I'm in favor of no PSA testing. I think that certainly if you have risk factors, that's reasonable. But for the average patient with very low or minimal risk factors, I am more in agreement with the USPS. STF in the sense that I don't know that that number needed to treat is convincing enough for me to want to do a PSA in a Dre test when I become of age. And I think that there's definitely risks to over treatment, especially with this kind of cancer, as opposed to breast cancer, where I think that the risk of over treatment may be a little bit less. Speaker 2 1:00:19 It's certainly a controversial issue, and it's something that a lot of men and their families are grappling with every day. And I don't have an easy answer for it. I will say I'm looking forward to seeing the results of the pivot study. This is a prostate interventional study that's ongoing right now where men who have low grade prostate cancers are being randomized to a watch and wait approach versus a treatment approach. And I think when we have some answers from that about maybe what would be the next step with an elevated PSA, then I would be more likely to recommend men go for testing. But right now, since the answer really is if you have a high PSA, we should follow it up, and we should pursue this until we have a diagnosis and we may need to treat you without knowing what difference that treatment is going to make. I have a hard time suggesting that men go down that path. It's not an easy answer. None of these are, but I'm glad we had the opportunity to discuss it and weigh the evidence on both sides. Dr. Sean Kane 1:01:17 For listeners, if you haven't done so already, we'd really appreciate a five star review on iTunes. You can find us at HelixTalk.com with that, I'm Dr. King, Unknown Speaker 1:01:26 I'm Dr. Hartranft, Speaker 3 1:01:27 and I'm Dr. Sherman. And on behalf of Dr. Patel, for all students out there, study hard, Narrator - Dr. Abel 1:01:34 thank you for listening to this episode of HelixTalk. For more information about the show, please visit us at HelixTalk.com you.