Dr. Journal Club
Dr. Journal Club
Mistletoe in Oncology: A Deep Dive into Pancreatic Cancer Trials
Could mistletoe be the unexpected key to fighting advanced pancreatic cancer? Join us as we explore the research behind mistletoe extract, Viscum album, and its potential in oncology. We'll delve into the MISTRAL trial, highlighting the herb's immunomodulating and anti-inflammatory properties, administration methods, and injection site reactions. We also critically examine the MAPAC trial, emphasizing the need for rigorous research in life-threatening conditions.
Tune in for an engaging discussion on the placebo-controlled trial evaluating mistletoe as an adjunct therapy for advanced exocrine pancreatic cancer. We'll break down the trial's design, challenges in maintaining blinding, participant functionality scores, and exclusion criteria. Our analysis includes comparing results with previous studies, geographic variations in end-of-life care, and the ceiling effect. Gain insights into mistletoe's safety and interaction with chemotherapy, and learn why well-conducted trials with negative outcomes are crucial for medical advancement. Don't miss this episode on integrating new interventions into clinical practice.
https://pubmed.ncbi.nlm.nih.gov/38915151/
Wode K, Kienle GS, Björ O, Fransson P, Sharp L, Elander NO, Bernhardson BM, Johansson B, Edwinsdotter Ardnor C, Scheibling U, Hök Nordberg J, Henriksson R. Mistletoe Extract in Patients With Advanced Pancreatic Cancer. Dtsch Arztebl Int. 2024 May 31;121(11):347-354. doi: 10.3238/arztebl.m2024.0080. PMID: 38915151.
Learn more and become a member at www.DrJournalClub.com
Check out our complete offerings of NANCEAC-approved Continuing Education Courses.
Welcome to the Dr Journal Club podcast, the show that goes under the hood of evidence-based integrative medicine. We review recent research articles, interview evidence-based medicine thought leaders and discuss the challenges and opportunities of integrating evidence-based and integrative medicine. Continue your learning after the show at www. journalclubcom.
Dr. Joshua Goldenberg:Please bear in mind that this is for educational and entertainment purposes. nly Talk to your doctor before making any medical decisions, changes etc. Everything we're talking about that's to teach you guys stuff and have fun. We are not your doctors. Also, we would love to answer your specific questions on drjournalclub. com. You can post questions and comments for specific videos, but go ahead and email us directly at josh at drjournalclubcom. That's josh at drjournalclubcom. Send us your listener questions and we will discuss it on our pod.
Dr. Joshua Goldenberg:All right, this is Josh and Adam reporting to you live, not live, Reporting to you about mistletoe. My dear colleague and listener, jacob shore, who is a amazing human, outstanding kayaker and naturopath, extraordinaire major leader in getting naturopaths on board with evidence-based medicine and looking at evidence from the get-go. So he's a listener and you should be too, and you are if you're listening. So that's not super helpful. Um, anyway, he recommended that we talk about this paper and, uh, it was a good one. Now, very rarely do I ever hear Adam say, oh, this is a good paper.
Dr. Adam Sadowski:Well, Josh.
Dr. Joshua Goldenberg:Let alone if it's recommended from a listener.
Dr. Adam Sadowski:So we might not have listeners. We might not have some listeners. We might have people who are like, oh, it's good background noise. We don't want to be background noise.
Dr. Joshua Goldenberg:Yeah, that's true. That's true. Yeah, they could. The numbers could be juiced by people, just like letting it play out or auto download or something. That's true. So, for those who are listening, this is a, this is a paper. We'll we'll do the show notes link mistletoe extract in patients with advanced pancreatic cancer. This is the mist, mistrial, mistrial. I was gonna. I want to say mistrial mish mistrial.
Dr. Adam Sadowski:Mistrial, yeah, but but yeah, it sounds like mistrial because it kind of was a mistrial yeah, yeah.
Dr. Joshua Goldenberg:So this, just when did this come out? This come out this year, or yep?
Dr. Adam Sadowski:2024, I believe it was in may 2024.
Dr. Joshua Goldenberg:Okay, cool, cool, cool, cool. You want to. You want to walk us through the uh background and methods, or how? How would you like to proceed, sir?
Dr. Adam Sadowski:Yeah, let's start off with some of the background, because, for anyone who's not aware, mistletoe, also known as viscum album, which is the Latin name, is basically an herb. Actually, it's not an herb, it's kind of like the way I think of it is like a moss that grows on trees a parasite or something right parasitic plant because it's a shrub but it's hemiparasitic and meaning it like feeds off of the the tree that's on it.
Dr. Adam Sadowski:The the most common one that that westerners are probably aware of is the european mistletoe and itoe and it's being looked at particularly in oncology settings because it has a mechanism of action where basically can be immunomodulating and some, you know, anti-inflammatory components to it and typically in these oncology settings it's being administered as an injection and the injections are. They can be pretty intense, which is one way that, like mistletoe, is kind of notorious in these oncology settings.
Dr. Joshua Goldenberg:Oh, what do you mean? That's interesting. I didn't know that. What happens?
Dr. Adam Sadowski:Yeah, it often has like an injection site reaction type of it's like a local skin irritation. It's pretty common with them, especially at higher doses. It is not FDA approved for treatment. We are not making a treatment recommendation. This is not medical advice. We're just educating people on this, by the way, and so there is some interesting research on it. However, a lot of the research has flaws from a methodological standpoint, so even anything that is sort of like interesting is really needs to be taken with a grain of salt, especially when you're using it for things like cancer very serious, very serious health conditions. Right.
Dr. Adam Sadowski:And in Europe it does seem to be not approved, but a little bit more utilized, if you will.
Dr. Joshua Goldenberg:Yeah, it sounded like it was a pretty regular thing to do and they were like trying to find locations I wouldn't say regular, but more well accepted amongst the community there. Yeah.
Dr. Adam Sadowski:And basically the basis of this trial is from data that came from a previous trial looking at the use of mistletoe for um cancer, specifically looking at like health-related quality of life and if it helped to extend life yeah um, and that that trial was conducted. I believe, uh, it was in one of the baltic states. I believe, uh, serbia, I want to say, or maybe Slovenia.
Dr. Adam Sadowski:It was known as the MAPAC trial, m-a-p-a-c. It was a trial with pretty robust results. However, again from a methodological standpoint, it was an open labeled randomized control trial, so there was no blinding and so you know know the results were likely um confounded there but, but, but, but, hold on, hold on, hold on, hold on, but I'm not sorry, not not confounded, but but inflated well, I mean maybe, but I mean maybe the the quality of life outcomes, but they saw a survival benefit.
Dr. Joshua Goldenberg:I think it's a hard, hard push to say blinding impacts, survival benefits. Well, I mean we would have to look at the trial. Look at, you know, look at that trial specifically benefit.
Dr. Adam Sadowski:I think it's a hard, hard push to say blinding impacts, survival benefits. Well, I mean we would have to look at the trial and look at you know look at that trial specifically to see yeah, yeah, yeah.
Dr. Joshua Goldenberg:So so to your, to your point like you had this promising study but there were flaws, and so this was meant to kind of like what? Like say, okay, let's do this, but do it even better and see if we still see the same effects exactly, yeah, and so that that one was done in 220 patients with advanced pancreatic cancer big, so big study and so in this trial they're essentially repeating exactly what was done um in that trial, uh in in participants with advanced pancreatic cancer, but being utilized in sweden specifically. And blinded.
Dr. Adam Sadowski:And blinded, yeah, so this was a much more rigorous trial. It was a double blinded, randomized, controlled trial where the blinding was basically everyone across the board was blinded. It was a publicly funded trial, which is great, so there was no industry sponsorship. However, did uh did provide supplies of of the mistletoe as well as placebo right and it seems like that.
Dr. Joshua Goldenberg:Maybe you know this better than I, but it seemed like there's like a very specific extract that is used from this company. Yes, and so I was. The whole time I was wondering, like, how do you know that you got the product right? But it sounds like they were using the standard extract that kind of everybody uses and that they used in this map hack study or whatever yeah, there's different ways of extracting it, so you can ferment mistletoe or not and then you can use, you know, aqueous solution.
Dr. Adam Sadowski:So are you extracting it in water? Are you extracting it using alcohol, like an alcohol base? Um, and I believe in this one. It was, uh, it was a fermented alcohol base, uh, and they got it specifically from an oak tree. So they were very, it was very like well, well, Described, characterized yeah.
Dr. Adam Sadowski:Resourced and how they described it and characterized it this way, which is good, because future trials really ought to do that of like. Okay, you know, I think that's part of the issue when it comes to like. Botanical medicine is okay. Well, what were the growing conditions? Where were they grown? You know, maybe you know basil, something like you know basil in new york might be different from from basil in italy or or something like that. You know, the growing conditions might be different.
Dr. Joshua Goldenberg:So yeah, and especially if it's parasitic on a tree, like it's important to know what tree it was growing on.
Dr. Adam Sadowski:Right, or any of the organisms that, like interacted with it. So there's, you know, there's a lot of things there that we need to take into consideration.
Dr. Joshua Goldenberg:So this was so just to. You already said this, but I just want to underline this. So it's not like they picked a random intervention. They used the same one that was very promising in this other study, and it's the same patient population too. It looks like the initial study was an advanced pancreatic cancer and this patient population is advanced pancreatic cancer, so it really was trying to confirm this very impressive finding, but in a more robust way, like there wasn't a lot of deviation that I saw between the study they were basing this on and this study.
Dr. Adam Sadowski:Exactly yeah. And and they also pick Sweden specifically, um, because Sweden has, according to these, to these authors, it's, it's more, uh, mislit was more widely recognized and they also have, uh, already like well integrated multidisciplinary oncology settings, and so it would just kind of, from a practical standpoint, be a little bit easier to carry out. From a logistic standpoint. You know that everything's already in place.
Dr. Joshua Goldenberg:Yeah, yeah, very cool. And I just a quick comment on the material. You said it was fermented. I I did. I mean, if I learned I must have learned that at in, in, at bastir. But like I I need not know that, I just not recall that. I mean, it's really kind of cool to think about like a fermented extract, very, very interesting, and I guess that's traditionally how it's been uh used. But anyway, yeah, so we got this uh and you had said it's different ways of extraction. It looks like this one was an aqueous extract.
Dr. Adam Sadowski:Exactly, and so the so the whole . point of this trial just to kind of uh, tie up some loose ends was that they're they're trying to see if adding on mistletoe extract administration to standard treatment, compared to placebo plus standard treatment right could prolong survival, overall survival, as well as health-related quality of life yeah in people with advanced pancreatic cancer and for this the standard treatment was palliative chemotherapy or just like best supportive care and palliative chemotherapy.
Dr. Adam Sadowski:Meaning you know you can there be a little bit of additional benefit in preventing, you know, further cancer growth but ultimately, knowing that you, basically you're so advanced that it's likely to, you know, likely going to end life. Pancreatic cancer is not one of those more forgiving cancers. The mortality rate is quite high with it, unfortunately, and so it's like okay if you're healthier and you can kind of withstand treatment, but we know that it's likely a terminal diagnosis, but we're trying to kind of get as much life extension as possible. Perhaps we can go forward with it. Yeah.
Dr. Adam Sadowski:Or your baseline might be pretty deteriorated and adding on more chemotherapies unlikely going to really either add much benefit to to quality of life, it may worsen it, or it may not extend life out with much significance. And so perhaps it really is just about overall, you know, providing best supportive care and letting them see out the best of their life. That's remaining.
Dr. Joshua Goldenberg:Yeah, absolutely. And yeah, advanced pancreatic cancer is not a good one. We're talking about maybe a few extra months of survival if things go well. Right, I think you know the other thing that you said this again, but I want to underline this is that this was in addition to sort of standard of care, but it's not one of these integrative studies that we're used to seeing where you've got standard of care and then one group gets additional integrative medicine. It's that or a placebo. So it's still a placebo controlled trial, and so we're basically saying, like, is adding this on any better than placebo when you already have all this other stuff on board? So again, this is not a A plus B versus A. It's A plus B versus A plus placebo B.
Dr. Adam Sadowski:Right. And the placebo was exactly identical to mistletoe in how it looked and how it would assume, how it would feel and how it was administered. So it was still, you know, injected and whatnot, which I think is important.
Dr. Joshua Goldenberg:Yeah, but to your point, man, like I think they mentioned that like, if you look at the adverse event, well, maybe I'm foreshadowing, but like when we jump later you said this it's very common to get these adverse reactions and they did see a dramatic difference in adverse reaction between the placebo and misotol duh and that. But that's a big concern for blinding, for masking, right, like, yeah, maybe it started off as blind, but you know, it would be very obvious to to medical staff and to perhaps the participants that they know to expect this if it didn't happen versus if it did happen. So we have to think a lot about even though it was placebo controlled. Did that blind last? Or was it unmasked during the trial? Right, right?
Dr. Adam Sadowski:No, I mean, I think it's a good point, but I mean but which way would that bias, though?
Dr. Joshua Goldenberg:right, like, which way would that bias that would bias towards benefit, right, because you would know that you got the mistletoe and so you might expect a better outcome. So you know, if this was a positive study, you might say, oh, maybe we've got an issue there. If this was a negative study, then again, it's not just that it's biased or potentially biased, it's the direction of expected bias. So, if anything, you would expect this to make things look rosier.
Dr. Adam Sadowski:But if the results are not rosy, then you don't really have to worry about it, because the but overall, if you have the chance to read this paper, I actually really like the way it was outlaid, how it was reported. I was surprised it was kind of in this obscure journal. Right. It was in a German journal. Yeah. But it was very well done. Yeah. It was very well done, very well reported. Yeah, this was an excellent read.
Dr. Joshua Goldenberg:You heard it here Adam likes the study and it's on integrative medicine and he likes the study but I agree it was super well done. I thought but and I was surprised by the I had the same thought. I was like, huh, if it's, you know, you think of small, like a randomized, controlled trial result in a small, or at least I don't know if it's small, but I didn't know about this journal, maybe 30 people or something. No, this is like a, you know, 300 person, randomized, controlled, conducted. You know you kind of expect this in BMJ or something.
Dr. Adam Sadowski:Yeah, but yeah, it was a. It was a double blind, randomized placebo controlled trial across nine different oncology centers in Sweden where people who had a recent diagnosis of advanced exocrine pancreatic cancer or a relapse of cancer and they did actually do analyses where, from a sensitivity analysis standpoint, um, tease that out of like, okay, do the results differ in people with new diagnosis versus a recurrent? And, just for sake of time, um, there was no difference when. When, looking at that and the people who entered the trial, um, they had, from a functionality standpoint we're a little bit on a less severe standpoint they have what's called the Eastern Cooperative Oncology Group Performance Status, or the ECOG, where lower scores indicate a healthier or more of like a robust health from a baseline standpoint. So if you had an ECOG score of one, that would be much better than someone a score of five is mortality. So if you were, you know, in this trial they recruited people with a baseline that was less than or equal to two.
Dr. Adam Sadowski:So people who, for the most part, are functioning well and if there's any sort of limitations they're not. They're still able to do like their activities of daily living and whatnot. They're not like completely decompensated. Uh, baseline Um, and they needed to have a life expectancy greater than four weeks. It makes sense for what they're trying to find with with this trial, and then, uh, basically just need them to not be pregnant, breastfeeding, all sort of like the kind of standard stuff, not using any sort of other immunomodulating things, agents, making sure that no one had, like an autoimmune disease, anything like that, or being treated for an autoimmune disease. I didn't really have any sort of issues with the inclusion-exclusion criteria, did you?
Dr. Joshua Goldenberg:No, not at all Pretty. I didn't really have any sort of issues with the inclusion exclusion criteria, did you? No, not at all. And they they tracked again very closely with this MAPAC trial, including for the intervention same intervention, same dosing, same adaptation of dosing. So again they're like this looks really promising.
Dr. Adam Sadowski:Let's see if we can repeat this with blinding Right People who were also excluded was really anyone who had a prior experience with mistletoe, or if they had any sort of known hypersensitivity to mistletoe components. Makes sense. Which probably means that they knew about this skin injection site reaction.
Dr. Joshua Goldenberg:Look, the thing is we don't do this for money. This is pro bono and, quite honestly, the mothership kind of ekes it out every month or so. Right, so we do this because we care about this, we think it's important, we think that integrating evidence-based medicine and integrative medicine is essential and there just aren't other resources out there the moment. We find something that does it better, we'll probably drop it. We're busy folks, but right now this is what's out there. Unfortunately, that's it, and so we're going to keep on fighting that good fight. And if you believe in that, if you believe in intellectual honesty in the profession and integrative medicine and being an integrative provider and bringing that into the integrative space, please help us, and you can help us by becoming a member on Dr Journal Club.
Dr. Joshua Goldenberg:If you're in need of continuing education credits, take our NANSEAC approved courses. We have ethics courses, pharmacy courses, general courses. Interact with us on social media, listen to the podcast, rate our podcast, tell your friends. These are all ways that you can sort of help support the cause.
Dr. Joshua Goldenberg:Yep, all makes sense. Got no problem with inclusion criteria or the intervention or the design. Oh, I just want to point out the design, so statistically. So they were very careful and did a good job about intention to treat analysis right. So they tracked loss to follow up and all that, but they actually analyzed as per the allocation, which is very, very important for intention to treat analysis, especially if there's differences in continuation of treatment, which there was here, which we'll get to in a second. But yeah, they did everything kosher from a ITT or intention to treat analysis perspective. They did also look at per protocol and report it separately in case people were interested too.
Dr. Adam Sadowski:But they're very clear on their primary outcome yeah, um, and then when they administered, uh, the mistletoe and the placebo, they basically titrated them up to the most, to the highest maximal dose, and then, uh, followed them up, um, basically on a on a monthly basis up until nine months, which was the end of the trial. And then the primary outcome that they looked at was overall survival, and then the secondary endpoint was health-related quality of life, and then other secondary endpoints that I thought were reasonable were glucocorticoid use, so, meaning like, did we have to use any sort of like salvage therapy to try to get you know kind of improve, sort of their function and and response to to treatment and the cancer? They looked at safety outcomes and then they they said that they were going to look up body weight. I wasn't able to find those results anywhere.
Dr. Joshua Goldenberg:They said they're going to publish them later. I think Publish them later, Okay. And then, yeah, they're going to publish them later.
Dr. Adam Sadowski:I think publish them later, okay, and then?
Dr. Joshua Goldenberg:yeah, they're saving their secondaries for another publication great um.
Dr. Adam Sadowski:And then they, they did um trial, or, excuse me, they did. They published not only their protocol um prior to this trial being done, but they also registered registered their trial in what looked like both European and US-based registries, which was really cool yeah.
Dr. Joshua Goldenberg:Yep, excellent. Yeah, they did a great job. No concerns whatsoever from a methods perspective, besides the concern for potential blinding, which is not a quality on them, it's just a manifestation of the intervention.
Dr. Adam Sadowski:Yep, basically they just needed 290 people in the trial, which is what they got, which is pretty consistent with the prior trial, which needed 220. So this one had 290, so a little bit more, but still consistent with everything. There were 143 people who were in the mistletoe extract group and 147 in the placebo group. Within the mistletoe extract, 140 received therapy and in the placebo group, 143 received therapy. 32 people discontinued intervention in the mistletoe group and really the majority of that is what I kind of understood as really just like treatment fatigue in general, which is pretty pragmatic of like people just saying, hey, you know what, I think I'm done with treatment and just kind of want to live out the rest of my life.
Dr. Joshua Goldenberg:Hmm, I had a different take on that, because if you look at the other side placebo, you only had 18 people discontinued versus you almost have double that.
Dr. Adam Sadowski:I thought it was because of the reactions but they did discontinue yeah, but twice as many people they did discontinue for basically the same reason, though right.
Dr. Joshua Goldenberg:So like that's the like, that's the question. So I think it was, I think it might have been the reaction. They didn't like the reaction, the localized reaction I'm trying to look here it might be me reading between the lines here, but there was a dramatic difference in the skin reaction. So like 93 out of 140 people who got the actual mistletoe had these skin reactions, versus like two people in the placebo group.
Dr. Adam Sadowski:So yeah, I tried, I tried, I guess I piece, tried to piece out e table one. Uh, at the end. But then I realized that that was for all the people who did not, who ultimately decided not to enter the trial, or they combined the two, so they didn't actually hash that out. So you might be right there. So that's a good point.
Dr. Joshua Goldenberg:Well, I guess the reason I'm harping on it is like, if you have an imbalance and the reason for the imbalance is related to the intervention or the outcome, you have a potential bias issue and the concern is this may be related to the intervention because it causes these, you know these reactions. Again, however, this would be a major concern if you did like a per protocol analysis or something like that they did, analyzed as as allocated, so that was all good. And again, the direction of this concern that I have would be to make things look rosier than they are, and if we don't see a rosy result, it's sort of a non-issue, but that's why I'm kind of harping on it. It's like we do see this doubling of dropouts and I think you can make an argument that the dropouts have to do with the intervention. It's not necessarily random.
Dr. Adam Sadowski:And we do also see that, you know, when, looking at both intention to treat and per protocol analysis, the results were essentially preserved.
Dr. Joshua Goldenberg:Yeah, that was cool. It's nice to also report per protocol, but just not harp on it, which is exactly what they did. They put it in an e-supplement, but they said that basically the results were the same. So, even with all these concerns, again, Yep and then at baseline.
Dr. Adam Sadowski:For the most part, the characteristics of participants was pretty well balanced, with the exception of a couple of changes here and there with regards to where people's cancer staging was at and whether or not they had a new diagnosis or if it was a relapse even did like, didn't they do like a sensitivity analysis later and said, no, that that won't impact the results either.
Dr. Joshua Goldenberg:Right, even though there are. Yeah, so that's common. Like if you do, you know you randomize people, but just by random chance sometimes the groups look different and you want to make sure that the results that you see are not because of that difference. So they did that as a sensitivity analysis and they did not see a signal there either.
Dr. Adam Sadowski:Yeah, I think they did four sensitivity analyses, um, looking at different things, um, and they just didn't find any really changes in the results, which is again uh, which is good from like the consistency standpoint and like how, how, how much can we believe in these results?
Dr. Joshua Goldenberg:so, yeah, okay, totally agree, love it, loving. So far, they did a really amazing job.
Dr. Adam Sadowski:Yeah, so when we look at the primary outcome, which was again overall survival compared to placebo, we saw that there was no, there was no difference. Yeah. The adjusted hazard interval was a 0.89 to a 1.44. And yeah it just. It just did not change.
Dr. Joshua Goldenberg:Yeah, it's a shame. And then, yeah, they did all the sensitivities about the same. Yeah.
Dr. Adam Sadowski:And actually from like a nominal standpoint. The median overall survival was 7.8 months in the mesothelial group versus 8.3 in the placebo arm.
Dr. Joshua Goldenberg:Right, so nominally, uh, even a little bit worse, but not statistically significantly different. Yeah.
Dr. Adam Sadowski:Yeah, exactly Uh. There was also no change uh in the health related quality of life compared to to to either group Um, and they had uh 99, 99 percent uh questionnaire completion rate.
Dr. Joshua Goldenberg:so yeah, and no loss to follow-up man. They had no loss to follow as a well-conducted study there's no, no loss of data there.
Dr. Adam Sadowski:I mean, if you look at figure two as well, uh, when they look at overall survival, um, from start of treatment to treatment period, to excuse me, end, end of the treatment period, so from from when they entered the trial until month nine, just looking at that, basically the lines are right on top of each other. There's no, there's no divergence, um, and then they said, okay, well, what if we do it for the entire follow-up period as well, after, after the the treatment was administered? And again we see no divergence at all. They're just basically on top of each other the entire time yep, yep, that's totally true.
Dr. Joshua Goldenberg:So it's like, okay, well, maybe, maybe the effects, uh, you know you need longer to see the effects and yeah, up to what, uh, four years later, right?
Dr. Adam Sadowski:um, no, no difference yeah, um, I thought that the discussion section, um, I did read it just to kind of see what Four years later, right, no, no difference. Yeah, I thought that the discussion section.
Dr. Joshua Goldenberg:I did read it just to kind of see what see if they would compare the results to the.
Dr. Adam Sadowski:You must have really liked the paper I did, and I wanted to see what like how they compare it to the MAPAC trial. I thought that they were very neutral in their tone as to how they compared to the MAPAC trial. Mm, hmm.
Dr. Joshua Goldenberg:Agree, yeah, they again. They just really. And they had some, you know, thoughtful analysis, which is what you're supposed to do, or thoughtful discussion, which is what you're supposed to do in this discussion, like, why did it work in that trial but not this one? So they talked about blinding is the obvious one, but they said you know differences between uh serbia and uh.
Dr. Joshua Goldenberg:you said sweden, right yep um, and I thought that was interesting, that they um, I might be stealing your thunder here, but that there might have been like a ceiling effect. So like in uh serve, let me see if I get this right, it's serbia, they said. There's not as much, it's not having this sort of a great care and um, end of life additional care is not common, and so there might have been additional benefits to glean from something like mistletoe, but that in Sweden it's very standardized to do all these advanced sort of end of life, advanced pancreatic cancer care, and so you might have already got all the benefit you could get from additional interventions and you sort of had that ceiling effect and the mistletoe was not able to add anything to that, which is also useful information. But so they conjectured a little bit on that. I thought that was that was interesting. I wouldn't. I don't think I would have thought of that on my own.
Dr. Adam Sadowski:Yeah, yeah, sometimes you know, when we read negative trials or quote, unquote negative, they're reported as negative because the results are not statistically significant. So people kind of view them as like, oh well, this doesn't really add to science. I really think the complete opposite, especially if it's something that's really well conducted, of like there was no bias really going into this paper. If anything, it was kind of mistletoe leaning. If anything, it was kind of mistletoe leaning and they were like, hey, we were actually kind of surprised with the results that we got, given just how robust the findings were in the mapac trial totally and like it's just, it's just an unfortunate finding.
Dr. Adam Sadowski:like they, they did a really good job, they got the product from the correct industry, they used a multidisciplinary team, they did every, they did everything right, like as much as you could, and so, yeah, there's just nothing there. Yeah, there's nothing there.
Dr. Adam Sadowski:You know, if we were to do a grade on this it would be high, right, we would probably have a high grade score and unlikely to change, you know, outcomes moving forward, at least when it comes to advanced pancreatic cancer. Now we can't say, well, this applied to, you know, breast cancer, colon cancer, any other types of cancer. We can really only say hey, in in a European patient population, you know, in a, at least in Sweden, if we're looking strictly at this. But now we have Sweden in one of the one of the you know Baltic states, that there there seems to be a, at least in Sweden, if we're looking strictly at this. But now we have Sweden in one of the one of the you know Baltic States, that there there seems to be a conflicting evidence. But the higher level of evidence is pointing towards a null effect. And uh, you know I would caution, based on these results, that perhaps you don't utilize this now if you are seeking it. Yeah.
Dr. Adam Sadowski:I don't know the authors did are seeking it. Yeah, I don't know. The authors did talk about that in the discussion of like hey, you know, people may be maybe wanting to use this and you know, you just have to kind of like let them know yeah, yeah, I think that's fair I think. I think what they reported was we know it's, it's, it's at least safe that it doesn't interact with the chemotherapy yeah, that's true.
Dr. Adam Sadowski:We didn't talk about that, that's true and that safety was really limited to these injection site reaction, these localized injection site reactions which were minor but otherwise we did not see any sort of significant harms. And if they are still adamant on wanting to use this, based on this data and and they do show the different types of chemotherapy regimens that were used that at least over this timeframe it appeared to be safe. However, we also know that clinical trials suck at reporting safety data.
Dr. Joshua Goldenberg:Yeah, that's true, rare safety data in particular, and so I don't know, I would take issue with, I think, the thought, your statement that maybe lean away from it. Just because, at the end of the day, we've got two trials, two randomized trials they're not huge, about 200, 300 people each the grade level, just from precision, because of the small size, would be low. You'd probably rank down once or twice just for that. And one of the studies was high risk of bias. So you know, I think still, even though this was a great study, still the grade level would probably be low for this result just because of the overall size.
Dr. Joshua Goldenberg:And you know it could be that. You know it could be null because of bias. That was in the initial trial and this was addressed. That it could be null because, hey, randomness and that's why we do meta-analyses could be different because of the patient populations, like they conjectured about access to palliative care. So these are all really good questions, but I think, at the end of the day, you now have a very good study conducted in a high resource available country that unfortunately did not see a signal at all with this intervention for advanced pancreatic cancer, despite promising previous results.
Dr. Adam Sadowski:And based on the language you used in this paper, a country and medical system. That is like kind of I don't know a caution to say in favor of, but accepting of of this intervention and like, again, everything was set up to like have this work and it didn't.
Dr. Joshua Goldenberg:That's right. I think that's true. I got that same take. It's like, oh, these people really thought this was going to work and they wanted to do it more rigorously, and I didn't see any bias. But it was like you know bias. But it was like, uh, you know, wasn't, certainly didn't see appear biased in the other direction, like one of those studies like we're just going to prove that this herb doesn't work, type of thing. I did not get that sense at all no, no, no.
Dr. Adam Sadowski:I think sometimes when you read the introductions of paper, you kind of like you can tell know where it's going. I'm like, all right, yeah, like this was this is going to be a negative trial, and they're going to set it up that way. And, yep, there are the results and it's a negative trial. And, oh, look at the conclusion Yep, yep, nope, yep, they did not want this to work. This was the opposite. They're like, hey, no, this might work, like we need to study this. There's a lot of, there's several meta-analyses looking at it and everything is like the quality of data is just not there.
Dr. Joshua Goldenberg:We're going to make some high quality data data and unfortunately, you don't like the way that the cake tastes. Yeah, yeah, no, that could be true. And then another interesting thing I find this idea of like why studies have divergent results fascinating. One argument that I've seen for why the more we study something, the less impressive it looks, is that you shift the population that you study, right. So sometimes you'll study the most severe cases first because there's no other option out there for them, and then you say, oh, it works for that, let's try it for moderate, let's try it for mild, and maybe it's just not as effective in those patient populations. That is not the case here, right? It appears to, at least to me, that study population was very similar, if not identical, to the previous trial that really was set up to ask the same question in a similar population, just in a different country. And that's the only difference, besides the blinding that we can kind of chat about, besides just it being randomly different. Right, right, right, right.
Dr. Adam Sadowski:Awesome.
Dr. Joshua Goldenberg:All right, ladies and gentlemen, that's what we have to say for mistletoe today. Thank you, dr Jacob Shore, for that great recommendation. You impressed, adam, and that's hard to do. All right, we'll talk to you later. Bye, everybody.
Dr. Joshua Goldenberg:If you enjoy this podcast, chances are that one of your colleagues and friends probably would as well. Please do us a favor and let them know about the podcast and, if you have a little bit of extra time, even just a few seconds, if you could rate us and review us on Apple Podcast or any other distributor, it would be greatly appreciated. It would mean a lot to us and help get the word out to other people that would really enjoy our content. Thank you, hey y'all. This is Josh.
Dr. Joshua Goldenberg:You know we talked about some really interesting stuff today. I think one of the things we're going to do that's relevant. There is a course we have on Dr Journal Club called the EBM Boot Camp. That's really meant for clinicians to sort of help them understand how to critically evaluate the literature, etc. Etc. Some of the things that we've been talking about today. Go ahead and check out the show notes link. We're going to link to it directly. I think it might be of interest. Don't forget to follow us on social and interact with us on social media at drjournalclub drjournalclub on Twitter, we're on Facebook, we're on LinkedIn, etc. Etc. So please reach out to us. We always love to talk to our fans and our listeners. If you have any specific questions you'd like to ask us about research, evidence, being a clinician, etc. Don't hesitate to ask. And then, of course, if you have any topics that you'd like us to cover on the pod, please let us know as well.
Introducer:Thank you for listening to the Doctor Journal Club podcast, the show that goes under the hood of evidence-based integrative medicine. We review recent research articles, interview evidence-based medicine thought leaders and discuss the challenges and opportunities of integrating evidence-based and integrative medicine. Be sure to visit wwwdocorjournalclubcom to learn more.