August 1, 2024 • 36 mins
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.
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Episode Transcript
Available transcripts are automatically generated. Complete accuracy is not guaranteed.
Introducer (00:02):
Welcome to the Dr Journal Club podcast, the show
that goes under the hood ofevidence-based integrative
medicine.
We review recent researcharticles, interview
evidence-based medicine thoughtleaders and discuss the
challenges and opportunities ofintegrating evidence-based and
integrative medicine.
Continue your learning afterthe show at www.
(00:24):
journalclubcom.
Dr. Joshua Goldenberg (00:31):
Please bear in mind that this is for
educational and entertainmentpurposes.
nly Talk to your doctor beforemaking any medical decisions,
changes etc.
Everything we're talking aboutthat's to teach you guys stuff
and have fun.
We are not your doctors.
Also, we would love to answeryour specific questions on
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com.
You can post questions andcomments for specific videos,
(00:55):
but go ahead and email usdirectly at josh at
drjournalclubcom.
That's josh at drjournalclubcom.
Send us your listener questionsand we will discuss it on our
pod.
All right, this is Josh and Adamreporting to you live, not
live, Reporting to you aboutmistletoe.
(01:20):
My dear colleague and listener,jacob shore, who is a amazing
human, outstanding kayaker andnaturopath, extraordinaire major
leader in getting naturopathson board with evidence-based
medicine and looking at evidencefrom the get-go.
So he's a listener and youshould be too, and you are if
you're listening.
So that's not super helpful.
(01:40):
Um, anyway, he recommended thatwe talk about this paper and,
uh, it was a good one.
Now, very rarely do I ever hearAdam say, oh, this is a good
paper.
Dr. Adam Sadowski (01:50):
Well, Josh.
Dr. Joshua Goldenberg (01:51):
Let alone if it's recommended from a
listener.
Dr. Adam Sadowski (01:55):
So we might not have listeners.
We might not have somelisteners.
We might have people who arelike, oh, it's good background
noise.
We don't want to be backgroundnoise.
Dr. Joshua Goldenberg (02:04):
Yeah, that's true.
That's true.
Yeah, they could.
The numbers could be juiced bypeople, just like letting it
play out or auto download orsomething.
That's true.
So, for those who are listening, this is a, this is a paper.
We'll we'll do the show noteslink mistletoe extract in
patients with advancedpancreatic cancer.
This is the mist, mistrial,mistrial.
I was gonna.
(02:25):
I want to say mistrial mishmistrial.
Dr. Adam Sadowski (02:27):
Mistrial, yeah, but but yeah, it sounds
like mistrial because it kind ofwas a mistrial yeah, yeah.
Dr. Joshua Goldenberg (02:33):
So this, just when did this come out?
This come out this year, or yep?
Dr. Adam Sadowski (02:37):
2024, I believe it was in may 2024.
Dr. Joshua Goldenberg (02:40):
Okay, cool, cool, cool, cool.
You want to.
You want to walk us through theuh background and methods, or
how?
How would you like to proceed,sir?
Dr. Adam Sadowski (02:48):
Yeah, let's start off with some of the
background, because, for anyonewho's not aware, mistletoe, also
known as viscum album, which isthe 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 thatgrows on trees a parasite or
something right parasitic plantbecause it's a shrub but it's
(03:11):
hemiparasitic and meaning itlike feeds off of the the tree
that's on it.
The the most common one thatthat westerners are probably
aware of is the europeanmistletoe and itoe and it's
being looked at particularly inoncology settings because it has
a mechanism of action wherebasically can be
(03:35):
immunomodulating and some, youknow, anti-inflammatory
components to it and typicallyin these oncology settings it's
being administered as aninjection and the injections are
.
They can be pretty intense,which is one way that, like
mistletoe, is kind of notoriousin these oncology settings.
Dr. Joshua Goldenberg (03:58):
Oh, what do you mean?
That's interesting.
I didn't know that.
What happens?
Dr. Adam Sadowski (04:01):
Yeah, it often has like an injection site
reaction type of it's like alocal skin irritation.
It's pretty common with them,especially at higher doses.
It is not FDA approved fortreatment.
We are not making a treatmentrecommendation.
This is not medical advice.
We're just educating people onthis, by the way, and so there
(04:21):
is some interesting research onit.
However, a lot of the researchhas flaws from a methodological
standpoint, so even anythingthat is sort of like interesting
is really needs to be takenwith a grain of salt, especially
when you're using it for thingslike cancer very serious, very
serious health conditions.
Right.
And in Europe it does seem to benot approved, but a little bit
(04:43):
more utilized, if you will.
Dr. Joshua Goldenberg (04:46):
Yeah, it sounded like it was a pretty
regular thing to do and theywere like trying to find
locations I wouldn't say regular, but more well accepted amongst
the community there.
Yeah.
Dr. Adam Sadowski (04:58):
And basically the basis of this trial is from
data that came from a previoustrial looking at the use of
mistletoe for um cancer,specifically looking at like
health-related quality of lifeand if it helped to extend life
yeah um, and that that trial wasconducted.
(05:19):
I believe, uh, it was in one ofthe baltic states.
I believe, uh, serbia, I wantto say, or maybe Slovenia.
It was known as the MAPAC trial,m-a-p-a-c.
It was a trial with prettyrobust results.
However, again from amethodological standpoint, it
was an open labeled randomizedcontrol trial, so there was no
(05:42):
blinding and so you know knowthe results were likely um
confounded there but, but, but,but, hold on, hold on, hold on,
hold on, but I'm not sorry, notnot confounded, but but inflated
well, I mean maybe, but I meanmaybe the the quality of life
outcomes, but they saw asurvival benefit.
Dr. Joshua Goldenberg (05:59):
I think it's a hard, hard push to say
blinding impacts, survivalbenefits.
Well, I mean we would have tolook at the trial.
Look at, you know, look at thattrial specifically benefit.
Dr. Adam Sadowski (06:04):
I think it's a hard, hard push to say
blinding impacts, survivalbenefits.
Well, I mean we would have tolook at the trial and look at
you know look at that trialspecifically to see yeah, yeah,
yeah.
Dr. Joshua Goldenberg (06:11):
So so to your, to your point like you had
this promising study but therewere 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 effectsexactly, yeah, and so that that
one was done in 220 patientswith advanced pancreatic cancer
big, so big study and so in thistrial they're essentially
(06:34):
repeating exactly what was doneum in that trial, uh in in
participants with advancedpancreatic cancer, but being
utilized in sweden specifically.
And blinded.
Dr. Adam Sadowski (06:45):
And blinded, yeah, so this was a much more
rigorous trial.
It was a double blinded,randomized, controlled trial
where the blinding was basicallyeveryone across the board was
blinded.
It was a publicly funded trial,which is great, so there was no
industry sponsorship.
However, did uh did providesupplies of of the mistletoe as
(07:06):
well as placebo right and itseems like that.
Dr. Joshua Goldenberg (07:09):
Maybe you know this better than I, but it
seemed like there's like a veryspecific 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 wereusing the standard extract that
kind of everybody uses and thatthey used in this map hack study
or whatever yeah, there'sdifferent ways of extracting it,
so you can ferment mistletoe ornot and then you can use, you
(07:32):
know, aqueous solution.
Dr. Adam Sadowski (07:33):
So are you extracting it in water?
Are you extracting it usingalcohol, like an alcohol base?
Um, and I believe in this one.
It was, uh, it was a fermentedalcohol base, uh, and they got
it specifically from an oak tree.
So they were very, it was verylike well, well, Described,
characterized yeah.
(07:54):
Resourced and how they describedit and characterized it this
way, which is good, becausefuture trials really ought to do
that of like.
Okay, you know, I think that'spart of the issue when it comes
to like.
Botanical medicine is okay.
Well, what were the growingconditions?
Where were they grown?
You know, maybe you know basil,something like you know basil
in new york might be differentfrom from basil in italy or or
(08:16):
something like that.
You know, the growingconditions might be different.
Dr. Joshua Goldenberg (08:19):
So yeah, and especially if it's parasitic
on a tree, like it's importantto know what tree it was growing
on.
Dr. Adam Sadowski (08:26):
Right, or any of the organisms that, like
interacted with it.
So there's, you know, there's alot of things there that we
need to take into consideration.
Dr. Joshua Goldenberg (08:36):
So this was so just to.
You already said this, but Ijust want to underline this.
So it's not like they picked arandom intervention.
They used the same one that wasvery promising in this other
study, and it's the same patientpopulation too.
It looks like the initial studywas an advanced pancreatic
cancer and this patientpopulation is advanced
pancreatic cancer, so it reallywas trying to confirm this very
(08:57):
impressive finding, but in amore robust way, like there
wasn't a lot of deviation that Isaw between the study they were
basing this on and this study.
Dr. Adam Sadowski (09:07):
Exactly yeah.
And and they also pick Swedenspecifically, um, because Sweden
has, according to these, tothese authors, it's, it's more,
uh, mislit was more widelyrecognized and they also have,
uh, already like well integratedmultidisciplinary oncology
settings, and so it would justkind of, from a practical
(09:29):
standpoint, be a little biteasier to carry out.
From a logistic standpoint.
You know that everything'salready in place.
Dr. Joshua Goldenberg (09:35):
Yeah, yeah, very cool.
And I just a quick comment onthe material.
You said it was fermented.
I I did.
I mean, if I learned I musthave 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 ofcool to think about like a
fermented extract, very, veryinteresting, and I guess that's
traditionally how it's been uhused.
(09:56):
But anyway, yeah, so we gotthis uh and you had said it's
different ways of extraction.
It looks like this one was anaqueous extract.
Dr. Adam Sadowski (10:03):
Exactly, and so the so the whole .
point of this trial just to kindof uh, tie up some loose ends
was that they're they're tryingto see if adding on mistletoe
extract administration tostandard treatment, compared to
placebo plus standard treatmentright could prolong survival,
(10:24):
overall survival, as well ashealth-related quality of life
yeah in people with advancedpancreatic cancer and for this
the standard treatment waspalliative chemotherapy or just
like best supportive care andpalliative chemotherapy.
Meaning you know you can therebe a little bit of additional
(10:46):
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 ofthose more forgiving cancers.
The mortality rate is quitehigh with it, unfortunately, and
(11:08):
so it's like okay if you'rehealthier and you can kind of
withstand treatment, but we knowthat it's likely a terminal
diagnosis, but we're trying tokind of get as much life
extension as possible.
Perhaps we can go forward withit.
Yeah.
Or your baseline might be prettydeteriorated and adding on more
chemotherapies unlikely goingto really either add much
(11:30):
benefit to to quality of life,it may worsen it, or it may not
extend life out with muchsignificance.
And so perhaps it really isjust about overall, you know,
providing best supportive careand letting them see out the
best of their life.
That's remaining.
Dr. Joshua Goldenberg (11:49):
Yeah, absolutely.
And yeah, advanced pancreaticcancer is not a good one.
We're talking about maybe a fewextra months of survival if
things go well.
Right, I think you know theother thing that you said this
again, but I want to underlinethis is that this was in
addition to sort of standard ofcare, but it's not one of these
(12:10):
integrative studies that we'reused to seeing where you've got
standard of care and then onegroup gets additional
integrative medicine.
It's that or a placebo.
So it's still a placebocontrolled trial, and so we're
basically saying, like, isadding this on any better than
placebo when you already haveall this other stuff on board?
So again, this is not a A plusB versus A.
(12:33):
It's A plus B versus A plusplacebo B.
Dr. Adam Sadowski (12:37):
Right.
And the placebo was exactlyidentical 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 (12:53):
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 toget these adverse reactions and
they did see a dramaticdifference in adverse reaction
between the placebo and misotolduh and that.
But that's a big concern forblinding, for masking, right,
like, yeah, maybe it started offas blind, but you know, it
(13:13):
would be very obvious to tomedical staff and to perhaps the
participants that they know toexpect this if it didn't happen
versus if it did happen.
So we have to think a lot abouteven though it was placebo
controlled.
Did that blind last?
Or was it unmasked during thetrial?
Right, right?
Dr. Adam Sadowski (13:31):
No, I mean, I think it's a good point, but I
mean but which way would thatbias, though?
Dr. Joshua Goldenberg (13:36):
right, like, which way would that bias
that would bias towards benefit,right, because you would know
that you got the mistletoe andso you might expect a better
outcome.
So you know, if this was apositive study, you might say,
oh, maybe we've got an issuethere.
If this was a negative study,then again, it's not just that
it's biased or potentiallybiased, it's the direction of
expected bias.
So, if anything, you wouldexpect this to make things look
(13:57):
rosier.
Dr. Adam Sadowski (13:58):
But if the results are not rosy, then you
don't really have to worry aboutit, because the but overall, if
you have the chance to readthis paper, I actually really
like the way it was outlaid, howit was reported.
I was surprised it was kind ofin this obscure journal.
Right.
It was in a German journal.
(14:18):
Yeah.
But it was very well done.
Yeah.
It was very well done, verywell reported.
Yeah, this was an excellentread.
Dr. Joshua Goldenberg (14:27):
You heard it here Adam likes the study
and it's on integrative medicineand he likes the study but I
agree it was super well done.
I thought but and I wassurprised by the I had the same
thought.
I was like, huh, if it's, youknow, you think of small, like a
randomized, controlled trialresult in a small, or at least I
don't know if it's small, but Ididn't know about this journal,
maybe 30 people or something.
No, this is like a, you know,300 person, randomized,
(14:48):
controlled, conducted.
You know you kind of expectthis in BMJ or something.
Dr. Adam Sadowski (14:53):
Yeah, but yeah, it was a.
It was a double blind,randomized placebo controlled
trial across nine differentoncology centers in Sweden where
people who had a recentdiagnosis of advanced exocrine
pancreatic cancer or a relapseof cancer and they did actually
do analyses where, from asensitivity analysis standpoint,
(15:14):
um, tease that out of like,okay, do the results differ in
people with new diagnosis versusa recurrent?
And, just for sake of time, um,there was no difference when.
When, looking at that and thepeople who entered the trial, um
, they had, from a functionalitystandpoint we're a little bit
on a less severe standpoint theyhave what's called the Eastern
(15:38):
Cooperative Oncology GroupPerformance Status, or the ECOG,
where lower scores indicate ahealthier or more of like a
robust health from a baselinestandpoint.
So if you had an ECOG score ofone, that would be much better
than someone a score of five ismortality.
So if you were, you know, inthis trial they recruited people
(16:01):
with a baseline that was lessthan or equal to two.
So people who, for the most part, are functioning well and if
there's any sort of limitationsthey're not.
They're still able to do liketheir activities of daily living
and whatnot.
They're not like completelydecompensated.
Uh, baseline Um, and theyneeded to have a life expectancy
greater than four weeks.
It makes sense for what they'retrying to find with with this
(16:24):
trial, and then, uh, basicallyjust need them to not be
pregnant, breastfeeding, allsort of like the kind of
standard stuff, not using anysort of other immunomodulating
things, agents, making sure thatno one had, like an autoimmune
disease, anything like that, orbeing treated for an autoimmune
(16:44):
disease.
I didn't really have any sortof issues with the
inclusion-exclusion criteria,did you?
Dr. Joshua Goldenberg (16:51):
No, not at all Pretty.
I didn't really have any sortof issues with the inclusion
exclusion criteria, did you?
No, not at all.
And they they tracked againvery closely with this MAPAC
trial, including for theintervention same intervention,
same dosing, same adaptation ofdosing.
So again they're like thislooks really promising.
Dr. Adam Sadowski (17:05):
Let's see if we can repeat this with blinding
Right People who were alsoexcluded was really anyone who
had a prior experience withmistletoe, or if they had any
sort of known hypersensitivityto mistletoe components.
Makes sense.
Which probably means that theyknew about this skin injection
site reaction.
Dr. Joshua Goldenberg (17:26):
Look, the thing is we don't do this for
money.
This is pro bono and, quitehonestly, the mothership kind of
ekes it out every month or so.
Right, so we do this because wecare about this, we think it's
important, we think thatintegrating evidence-based
medicine and integrativemedicine is essential and there
just aren't other resources outthere the moment.
(17:46):
We find something that does itbetter, we'll probably drop it.
We're busy folks, but right nowthis is what's out there.
Unfortunately, that's it, andso we're going to keep on
fighting that good fight.
And if you believe in that, ifyou believe in intellectual
honesty in the profession andintegrative medicine and being
an integrative provider andbringing that into the
integrative space, please helpus, and you can help us by
(18:08):
becoming a member on Dr JournalClub.
If you're in need of continuingeducation credits, take our
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We have ethics courses,pharmacy courses, general
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Interact with us on socialmedia, listen to the podcast,
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These are all ways that you cansort of help support the cause.
(18:31):
Yep, all makes sense.
Got no problem with inclusioncriteria or the intervention or
the design.
Oh, I just want to point outthe design, so statistically.
So they were very careful anddid a good job about intention
to treat analysis right.
So they tracked loss to followup and all that, but they
actually analyzed as per theallocation, which is very, very
important for intention to treatanalysis, especially if there's
(18:53):
differences in continuation oftreatment, which there was here,
which we'll get to in a second.
But yeah, they did everythingkosher from a ITT or intention
to treat analysis perspective.
They did also look at perprotocol and report it
separately in case people wereinterested too.
Dr. Adam Sadowski (19:09):
But they're very clear on their primary
outcome yeah, um, and then whenthey administered, uh, the
mistletoe and the placebo, theybasically titrated them up to
the most, to the highest maximaldose, and then, uh, followed
them up, um, basically on a on amonthly basis up until nine
months, which was the end of thetrial.
(19:32):
And then the primary outcomethat they looked at was overall
survival, and then the secondaryendpoint was health-related
quality of life, and then othersecondary endpoints that I
thought were reasonable wereglucocorticoid use, so, meaning
like, did we have to use anysort of like salvage therapy to
try to get you know kind ofimprove, sort of their function
(19:55):
and and response to to treatmentand the cancer?
They looked at safety outcomesand then they they said that
they were going to look up bodyweight.
I wasn't able to find thoseresults anywhere.
Dr. Joshua Goldenberg (20:07):
They said they're going to publish them
later.
I think Publish them later,Okay.
And then, yeah, they're goingto publish them later.
Dr. Adam Sadowski (20:10):
I think publish them later, okay, and
then?
Dr. Joshua Goldenberg (20:14):
yeah, they're saving their secondaries
for another publication greatum.
Dr. Adam Sadowski (20:19):
And then they , they did um trial, or, excuse
me, they did.
They published not only theirprotocol um prior to this trial
being done, but they alsoregistered registered their
trial in what looked like bothEuropean and US-based registries
, which was really cool yeah.
Dr. Joshua Goldenberg (20:37):
Yep, excellent.
Yeah, they did a great job.
No concerns whatsoever from amethods perspective, besides the
concern for potential blinding,which is not a quality on them,
it's just a manifestation ofthe intervention.
Dr. Adam Sadowski (20:50):
Yep, basically they just needed 290
people in the trial, which iswhat they got, which is pretty
consistent with the prior trial,which needed 220.
So this one had 290, so alittle bit more, but still
consistent with everything.
There were 143 people who werein the mistletoe extract group
and 147 in the placebo group.
(21:11):
Within the mistletoe extract,140 received therapy and in the
placebo group, 143 receivedtherapy.
32 people discontinuedintervention in the mistletoe
group and really the majority ofthat is what I kind of
understood as really just liketreatment fatigue in general,
(21:32):
which is pretty pragmatic oflike people just saying, hey,
you know what, I think I'm donewith treatment and just kind of
want to live out the rest of mylife.
Dr. Joshua Goldenberg (21:40):
Hmm, I had a different take on that,
because if you look at the otherside placebo, you only had 18
people discontinued versus youalmost have double that.
Dr. Adam Sadowski (21:49):
I thought it was because of the reactions but
they did discontinue yeah, buttwice as many people they did
discontinue for basically thesame reason, though right.
Dr. Joshua Goldenberg (21:58):
So like that's the like, that's the
question.
So I think it was, I think itmight have been the reaction.
They didn't like the reaction,the localized reaction I'm
trying to look here it might beme reading between the lines
here, but there was a dramaticdifference in the skin reaction.
So like 93 out of 140 peoplewho got the actual mistletoe had
these skin reactions, versuslike two people in the placebo
(22:21):
group.
Dr. Adam Sadowski (22:22):
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 thatwas for all the people who did
not, who ultimately decided notto enter the trial, or they
combined the two, so they didn'tactually hash that out.
So you might be right there.
(22:42):
So that's a good point.
Dr. Joshua Goldenberg (22:45):
Well, I guess the reason I'm harping on
it is like, if you have animbalance and the reason for the
imbalance is related to theintervention or the outcome, you
have a potential bias issue andthe concern is this may be
related to the interventionbecause it causes these, you
know these reactions.
Again, however, this would be amajor concern if you did like a
(23:05):
per protocol analysis orsomething like that they did,
analyzed as as allocated, sothat was all good.
And again, the direction ofthis concern that I have would
be to make things look rosierthan they are, and if we don't
see a rosy result, it's sort ofa non-issue, but that's why I'm
kind of harping on it.
It's like we do see thisdoubling of dropouts and I think
(23:26):
you can make an argument thatthe dropouts have to do with the
intervention.
It's not necessarily random.
Dr. Adam Sadowski (23:33):
And we do also see that, you know, when,
looking at both intention totreat and per protocol analysis,
the results were essentiallypreserved.
Dr. Joshua Goldenberg (23:40):
Yeah, that was cool.
It's nice to also report perprotocol, but just not harp on
it, which is exactly what theydid.
They put it in an e-supplement,but they said that basically
the results were the same.
So, even with all theseconcerns, again, Yep and then at
baseline.
Dr. Adam Sadowski (23:58):
For the most part, the characteristics of
participants was pretty wellbalanced, with the exception of
a couple of changes here andthere with regards to where
people's cancer staging was atand whether or not they had a
new diagnosis or if it was arelapse even did like, didn't
they do like a sensitivityanalysis later and said, no,
(24:20):
that that won't impact theresults either.
Dr. Joshua Goldenberg (24:22):
Right, even though there are.
Yeah, so that's common.
Like if you do, you know yourandomize people, but just by
random chance sometimes thegroups look different and you
want to make sure that theresults that you see are not
because of that difference.
So they did that as asensitivity analysis and they
did not see a signal thereeither.
Dr. Adam Sadowski (24:40):
Yeah, I think they did four sensitivity
analyses, um, looking atdifferent things, um, and they
just didn't find any reallychanges in the results, which is
again uh, which is good fromlike the consistency standpoint
and like how, how, how much canwe believe in these results?
Dr. Joshua Goldenberg (24:54):
so, yeah, okay, totally agree, love it,
loving.
So far, they did a reallyamazing job.
Dr. Adam Sadowski (25:02):
Yeah, so when we look at the primary outcome,
which was again overallsurvival compared to placebo, we
saw that there was no, therewas no difference.
Yeah.
The adjusted hazard intervalwas a 0.89 to a 1.44.
(25:22):
And yeah it just.
It just did not change.
Dr. Joshua Goldenberg (25:27):
Yeah, it's a shame.
And then, yeah, they did allthe sensitivities about the same
.
Yeah.
Dr. Adam Sadowski (25:32):
And actually from like a nominal standpoint.
The median overall survival was7.8 months in the mesothelial
group versus 8.3 in the placeboarm.
Dr. Joshua Goldenberg (25:42):
Right, so nominally, uh, even a little
bit worse, but not statisticallysignificantly different.
Yeah.
Dr. Adam Sadowski (25:48):
Yeah, exactly Uh.
There was also no change uh inthe health related quality of
life compared to to to eithergroup Um, and they had uh 99, 99
percent uh questionnairecompletion rate.
Dr. Joshua Goldenberg (26:01):
so yeah, and no loss to follow-up man.
They had no loss to follow as awell-conducted study there's no
, no loss of data there.
Dr. Adam Sadowski (26:09):
I mean, if you look at figure two as well,
uh, when they look at overallsurvival, um, from start of
treatment to treatment period,to excuse me, end, end of the
treatment period, so from fromwhen they entered the trial
until month nine, just lookingat that, basically the lines are
(26:32):
right on top of each other.
There's no, there's nodivergence, um, and then they
said, okay, well, what if we doit for the entire follow-up
period as well, after, after thethe treatment was administered?
And again we see no divergenceat all.
They're just basically on topof each other the entire time
yep, yep, that's totally true.
Dr. Joshua Goldenberg (26:48):
So it's like, okay, well, maybe, maybe
the effects, uh, you know youneed longer to see the effects
and yeah, up to what, uh, fouryears later, right?
Dr. Adam Sadowski (26:57):
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 thediscussion section.
Dr. Joshua Goldenberg (27:07):
I did read it just to kind of see what
see if they would compare theresults to the.
Dr. Adam Sadowski (27:11):
You must have really liked the paper I did,
and I wanted to see what likehow they compare it to the MAPAC
trial.
I thought that they were veryneutral in their tone as to how
they compared to the MAPAC trial.
Mm, hmm.
Dr. Joshua Goldenberg (27:23):
Agree, yeah, they again.
They just really.
And they had some, you know,thoughtful analysis, which is
what you're supposed to do, orthoughtful discussion, which is
what you're supposed to do inthis discussion, like, why did
it work in that trial but notthis one?
So they talked about blindingis the obvious one, but they
said you know differencesbetween uh serbia and uh.
you said sweden, right yep um,and I thought that was
(27:44):
interesting, that they um, Imight be stealing your thunder
here, but that there might havebeen like a ceiling effect.
So like in uh serve, let me seeif I get this right, it's
serbia, they said.
There's not as much, it's nothaving this sort of a great care
and um, end of life additionalcare is not common, and so there
might have been additionalbenefits to glean from something
(28:06):
like mistletoe, but that inSweden it's very standardized to
do all these advanced sort ofend of life, advanced pancreatic
cancer care, and so you mighthave already got all the benefit
you could get from additionalinterventions and you sort of
had that ceiling effect and themistletoe was not able to add
anything to that, which is alsouseful information.
(28:26):
But so they conjectured alittle bit on that.
I thought that was that wasinteresting.
I wouldn't.
I don't think I would havethought of that on my own.
Dr. Adam Sadowski (28:34):
Yeah, yeah, sometimes you know, when we read
negative trials or quote,unquote negative, they're
reported as negative because theresults are not statistically
significant.
So people kind of view them aslike, oh well, this doesn't
really add to science.
I really think the completeopposite, especially if it's
something that's really wellconducted, of like there was no
bias really going into thispaper.
(28:55):
If anything, it was kind ofmistletoe leaning.
If anything, it was kind ofmistletoe leaning and they were
like, hey, we were actually kindof surprised with the results
that we got, given just howrobust the findings were in the
mapac trial totally and likeit's just, it's just an
unfortunate finding.
like they, they did a reallygood job, they got the product
from the correct industry, theyused a multidisciplinary team,
(29:19):
they did every, they dideverything right, like as much
as you could, and so, yeah,there's just nothing there.
Yeah, there's nothing there.
You know, if we were to do agrade on this it would be high,
right, we would probably have ahigh grade score and unlikely to
change, you know, outcomesmoving forward, at least when it
(29:40):
comes to advanced pancreaticcancer.
Now we can't say, well, thisapplied to, you know, breast
cancer, colon cancer, any othertypes of cancer.
We can really only say hey, inin a European patient population
, you know, in a, at least inSweden, if we're looking
strictly at this.
But now we have Sweden in oneof the one of the you know
(30:01):
Baltic states, that there thereseems to be a, at least in
Sweden, if we're lookingstrictly at this.
But now we have Sweden in oneof the one of the you know
Baltic States, that there thereseems to be a conflicting
evidence.
But the higher level ofevidence is pointing towards a
null effect.
And uh, you know I wouldcaution, based on these results,
that perhaps you don't utilizethis now if you are seeking it.
Yeah.
(30:22):
I don't know the authors did areseeking it.
Yeah, I don't know.
The authors did talk about thatin the discussion of like hey,
you know, people may be maybewanting to use this and you know
, you just have to kind of likelet them know yeah, yeah, I
think that's fair I think.
I think what they reported waswe know it's, it's, it's at
least safe that it doesn'tinteract with the chemotherapy
yeah, that's true.
We didn't talk about that,that's true and that safety was
(30:45):
really limited to theseinjection site reaction, these
localized injection sitereactions which were minor but
otherwise we did not see anysort of significant harms.
And if they are still adamanton wanting to use this, based on
this data and and they do showthe different types of
chemotherapy regimens that wereused that at least over this
timeframe it appeared to be safe.
(31:07):
However, we also know thatclinical trials suck at
reporting safety data.
Dr. Joshua Goldenberg (31:11):
Yeah, that's true, rare safety data in
particular, and so I don't know, I would take issue with, I
think, the thought, yourstatement that maybe lean away
from it.
Just because, at the end of theday, we've got two trials, two
randomized trials they're nothuge, about 200, 300 people each
the grade level, just fromprecision, because of the small
(31:33):
size, would be low.
You'd probably rank down onceor twice just for that.
And one of the studies was highrisk of bias.
So you know, I think still,even though this was a great
study, still the grade levelwould probably be low for this
result just because of theoverall size.
And you know it could be that.
You know it could be nullbecause of bias.
(31:54):
That was in the initial trialand this was addressed.
That it could be null because,hey, randomness and that's why
we do meta-analyses could bedifferent because of the patient
populations, like theyconjectured about access to
palliative care.
So these are all really goodquestions, but I think, at the
end of the day, you now have avery good study conducted in a
(32:15):
high resource available countrythat unfortunately did not see a
signal at all with thisintervention for advanced
pancreatic cancer, despitepromising previous results.
Dr. Adam Sadowski (32:28):
And based on the language you used in this
paper, a country and medicalsystem.
That is like kind of I don'tknow a caution to say in favor
of, but accepting of of thisintervention and like, again,
everything was set up to likehave this work and it didn't.
Dr. Joshua Goldenberg (32:48):
That's right.
I think that's true.
I got that same take.
It's like, oh, these peoplereally thought this was going to
work and they wanted to do itmore 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 otherdirection, like one of those
studies like we're just going toprove that this herb doesn't
work, type of thing.
I did not get that sense at allno, no, no.
Dr. Adam Sadowski (33:06):
I think sometimes when you read the
introductions of paper, you kindof like you can tell know where
it's going.
I'm like, all right, yeah, likethis was this is going to be a
negative trial, and they'regoing to set it up that way.
And, yep, there are the resultsand it's a negative trial.
And, oh, look at the conclusionYep, yep, nope, yep, they did
not want this to work.
This was the opposite.
They're like, hey, no, thismight work, like we need to
study this.
There's a lot of, there'sseveral meta-analyses looking at
(33:28):
it and everything is like thequality of data is just not
there.
Dr. Joshua Goldenberg (33:32):
We're going to make some high quality
data data and unfortunately, youdon't like the way that the
cake tastes.
Yeah, yeah, no, that could betrue.
And then another interestingthing I find this idea of like
why studies have divergentresults fascinating.
One argument that I've seen forwhy the more we study something
(33:53):
, the less impressive it looks,is that you shift the population
that you study, right.
So sometimes you'll study themost severe cases first because
there's no other option outthere for them, and then you say
, oh, it works for that, let'stry it for moderate, let's try
it for mild, and maybe it's justnot 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
(34:13):
similar, if not identical, tothe previous trial that really
was set up to ask the samequestion 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, besidesjust it being randomly different
.
Right, right, right, right.
Dr. Adam Sadowski (34:32):
Awesome.
Dr. Joshua Goldenberg (34:33):
All right , ladies and gentlemen, that's
what we have to say formistletoe today.
Thank you, dr Jacob Shore, forthat great recommendation.
You impressed, adam, and that'shard to do.
All right, we'll talk to youlater.
Bye, everybody.
If you enjoy this podcast,chances are that one of your
colleagues and friends probablywould as well.
(34:54):
Please do us a favor and letthem know about the podcast and,
if you have a little bit ofextra time, even just a few
seconds, if you could rate usand review us on Apple Podcast
or any other distributor, itwould be greatly appreciated.
It would mean a lot to us andhelp get the word out to other
people that would really enjoyour content.
Thank you, hey y'all.
This is Josh.
You know we talked about somereally interesting stuff today.
(35:14):
I think one of the things we'regoing to do that's relevant.
There is a course we have on DrJournal Club called the EBM
Boot Camp.
That's really meant forclinicians to sort of help them
understand how to criticallyevaluate the literature, etc.
Etc.
Some of the things that we'vebeen talking about today.
Go ahead and check out the shownotes link.
We're going to link to itdirectly.
I think it might be of interest.
(35:35):
Don't forget to follow us onsocial and interact with us on
social media at drjournalclubdrjournalclub on Twitter, we're
on Facebook, we're on LinkedIn,etc.
Etc.
So please reach out to us.
We always love to talk to ourfans and our listeners.
If you have any specificquestions you'd like to ask us
about research, evidence, beinga clinician, etc.
(35:55):
Don't hesitate to ask.
And then, of course, if youhave any topics that you'd like
us to cover on the pod, pleaselet us know as well.
Introducer (36:05):
Thank you for listening to the Doctor Journal
Club podcast, the show that goesunder the hood of
evidence-based integrativemedicine.
We review recent researcharticles, interview
evidence-based medicine thoughtleaders and discuss the
challenges and opportunities ofintegrating evidence-based and
integrative medicine.
Be sure to visitwwwdocorjournalclubcom to learn
(36:28):
more.
Welcome to the Dr Journal Club podcast, the show
that goes under the hood ofevidence-based integrative
medicine.
We review recent researcharticles, interview
evidence-based medicine thoughtleaders and discuss the
challenges and opportunities ofintegrating evidence-based and
integrative medicine.
Continue your learning afterthe show at www.
(00:24):
journalclubcom.
Dr. Joshua Goldenberg (00:31):
Please bear in mind that this is for
educational and entertainmentpurposes.
nly Talk to your doctor beforemaking any medical decisions,
changes etc.
Everything we're talking aboutthat's to teach you guys stuff
and have fun.
We are not your doctors.
Also, we would love to answeryour specific questions on
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com.
You can post questions andcomments for specific videos,
(00:55):
but go ahead and email usdirectly at josh at
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That's josh at drjournalclubcom.
Send us your listener questionsand we will discuss it on our
pod.
All right, this is Josh and Adamreporting to you live, not
live, Reporting to you aboutmistletoe.
(01:20):
My dear colleague and listener,jacob shore, who is a amazing
human, outstanding kayaker andnaturopath, extraordinaire major
leader in getting naturopathson board with evidence-based
medicine and looking at evidencefrom the get-go.
So he's a listener and youshould be too, and you are if
you're listening.
So that's not super helpful.
(01:40):
Um, anyway, he recommended thatwe talk about this paper and,
uh, it was a good one.
Now, very rarely do I ever hearAdam say, oh, this is a good
paper.
Dr. Adam Sadowski (01:50):
Well, Josh.
Dr. Joshua Goldenberg (01:51):
Let alone if it's recommended from a
listener.
Dr. Adam Sadowski (01:55):
So we might not have listeners.
We might not have somelisteners.
We might have people who arelike, oh, it's good background
noise.
We don't want to be backgroundnoise.
Dr. Joshua Goldenberg (02:04):
Yeah, that's true.
That's true.
Yeah, they could.
The numbers could be juiced bypeople, just like letting it
play out or auto download orsomething.
That's true.
So, for those who are listening, this is a, this is a paper.
We'll we'll do the show noteslink mistletoe extract in
patients with advancedpancreatic cancer.
This is the mist, mistrial,mistrial.
I was gonna.
(02:25):
I want to say mistrial mishmistrial.
Dr. Adam Sadowski (02:27):
Mistrial, yeah, but but yeah, it sounds
like mistrial because it kind ofwas a mistrial yeah, yeah.
Dr. Joshua Goldenberg (02:33):
So this, just when did this come out?
This come out this year, or yep?
Dr. Adam Sadowski (02:37):
2024, I believe it was in may 2024.
Dr. Joshua Goldenberg (02:40):
Okay, cool, cool, cool, cool.
You want to.
You want to walk us through theuh background and methods, or
how?
How would you like to proceed,sir?
Dr. Adam Sadowski (02:48):
Yeah, let's start off with some of the
background, because, for anyonewho's not aware, mistletoe, also
known as viscum album, which isthe 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 thatgrows on trees a parasite or
something right parasitic plantbecause it's a shrub but it's
(03:11):
hemiparasitic and meaning itlike feeds off of the the tree
that's on it.
The the most common one thatthat westerners are probably
aware of is the europeanmistletoe and itoe and it's
being looked at particularly inoncology settings because it has
a mechanism of action wherebasically can be
(03:35):
immunomodulating and some, youknow, anti-inflammatory
components to it and typicallyin these oncology settings it's
being administered as aninjection and the injections are
.
They can be pretty intense,which is one way that, like
mistletoe, is kind of notoriousin these oncology settings.
Dr. Joshua Goldenberg (03:58):
Oh, what do you mean?
That's interesting.
I didn't know that.
What happens?
Dr. Adam Sadowski (04:01):
Yeah, it often has like an injection site
reaction type of it's like alocal skin irritation.
It's pretty common with them,especially at higher doses.
It is not FDA approved fortreatment.
We are not making a treatmentrecommendation.
This is not medical advice.
We're just educating people onthis, by the way, and so there
(04:21):
is some interesting research onit.
However, a lot of the researchhas flaws from a methodological
standpoint, so even anythingthat is sort of like interesting
is really needs to be takenwith a grain of salt, especially
when you're using it for thingslike cancer very serious, very
serious health conditions.
Right.
And in Europe it does seem to benot approved, but a little bit
(04:43):
more utilized, if you will.
Dr. Joshua Goldenberg (04:46):
Yeah, it sounded like it was a pretty
regular thing to do and theywere like trying to find
locations I wouldn't say regular, but more well accepted amongst
the community there.
Yeah.
Dr. Adam Sadowski (04:58):
And basically the basis of this trial is from
data that came from a previoustrial looking at the use of
mistletoe for um cancer,specifically looking at like
health-related quality of lifeand if it helped to extend life
yeah um, and that that trial wasconducted.
(05:19):
I believe, uh, it was in one ofthe baltic states.
I believe, uh, serbia, I wantto say, or maybe Slovenia.
It was known as the MAPAC trial,m-a-p-a-c.
It was a trial with prettyrobust results.
However, again from amethodological standpoint, it
was an open labeled randomizedcontrol trial, so there was no
(05:42):
blinding and so you know knowthe results were likely um
confounded there but, but, but,but, hold on, hold on, hold on,
hold on, but I'm not sorry, notnot confounded, but but inflated
well, I mean maybe, but I meanmaybe the the quality of life
outcomes, but they saw asurvival benefit.
Dr. Joshua Goldenberg (05:59):
I think it's a hard, hard push to say
blinding impacts, survivalbenefits.
Well, I mean we would have tolook at the trial.
Look at, you know, look at thattrial specifically benefit.
Dr. Adam Sadowski (06:04):
I think it's a hard, hard push to say
blinding impacts, survivalbenefits.
Well, I mean we would have tolook at the trial and look at
you know look at that trialspecifically to see yeah, yeah,
yeah.
Dr. Joshua Goldenberg (06:11):
So so to your, to your point like you had
this promising study but therewere 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 effectsexactly, yeah, and so that that
one was done in 220 patientswith advanced pancreatic cancer
big, so big study and so in thistrial they're essentially
(06:34):
repeating exactly what was doneum in that trial, uh in in
participants with advancedpancreatic cancer, but being
utilized in sweden specifically.
And blinded.
Dr. Adam Sadowski (06:45):
And blinded, yeah, so this was a much more
rigorous trial.
It was a double blinded,randomized, controlled trial
where the blinding was basicallyeveryone across the board was
blinded.
It was a publicly funded trial,which is great, so there was no
industry sponsorship.
However, did uh did providesupplies of of the mistletoe as
(07:06):
well as placebo right and itseems like that.
Dr. Joshua Goldenberg (07:09):
Maybe you know this better than I, but it
seemed like there's like a veryspecific 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 wereusing the standard extract that
kind of everybody uses and thatthey used in this map hack study
or whatever yeah, there'sdifferent ways of extracting it,
so you can ferment mistletoe ornot and then you can use, you
(07:32):
know, aqueous solution.
Dr. Adam Sadowski (07:33):
So are you extracting it in water?
Are you extracting it usingalcohol, like an alcohol base?
Um, and I believe in this one.
It was, uh, it was a fermentedalcohol base, uh, and they got
it specifically from an oak tree.
So they were very, it was verylike well, well, Described,
characterized yeah.
(07:54):
Resourced and how they describedit and characterized it this
way, which is good, becausefuture trials really ought to do
that of like.
Okay, you know, I think that'spart of the issue when it comes
to like.
Botanical medicine is okay.
Well, what were the growingconditions?
Where were they grown?
You know, maybe you know basil,something like you know basil
in new york might be differentfrom from basil in italy or or
(08:16):
something like that.
You know, the growingconditions might be different.
Dr. Joshua Goldenberg (08:19):
So yeah, and especially if it's parasitic
on a tree, like it's importantto know what tree it was growing
on.
Dr. Adam Sadowski (08:26):
Right, or any of the organisms that, like
interacted with it.
So there's, you know, there's alot of things there that we
need to take into consideration.
Dr. Joshua Goldenberg (08:36):
So this was so just to.
You already said this, but Ijust want to underline this.
So it's not like they picked arandom intervention.
They used the same one that wasvery promising in this other
study, and it's the same patientpopulation too.
It looks like the initial studywas an advanced pancreatic
cancer and this patientpopulation is advanced
pancreatic cancer, so it reallywas trying to confirm this very
(08:57):
impressive finding, but in amore robust way, like there
wasn't a lot of deviation that Isaw between the study they were
basing this on and this study.
Dr. Adam Sadowski (09:07):
Exactly yeah.
And and they also pick Swedenspecifically, um, because Sweden
has, according to these, tothese authors, it's, it's more,
uh, mislit was more widelyrecognized and they also have,
uh, already like well integratedmultidisciplinary oncology
settings, and so it would justkind of, from a practical
(09:29):
standpoint, be a little biteasier to carry out.
From a logistic standpoint.
You know that everything'salready in place.
Dr. Joshua Goldenberg (09:35):
Yeah, yeah, very cool.
And I just a quick comment onthe material.
You said it was fermented.
I I did.
I mean, if I learned I musthave 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 ofcool to think about like a
fermented extract, very, veryinteresting, and I guess that's
traditionally how it's been uhused.
(09:56):
But anyway, yeah, so we gotthis uh and you had said it's
different ways of extraction.
It looks like this one was anaqueous extract.
Dr. Adam Sadowski (10:03):
Exactly, and so the so the whole .
point of this trial just to kindof uh, tie up some loose ends
was that they're they're tryingto see if adding on mistletoe
extract administration tostandard treatment, compared to
placebo plus standard treatmentright could prolong survival,
(10:24):
overall survival, as well ashealth-related quality of life
yeah in people with advancedpancreatic cancer and for this
the standard treatment waspalliative chemotherapy or just
like best supportive care andpalliative chemotherapy.
Meaning you know you can therebe a little bit of additional
(10:46):
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 ofthose more forgiving cancers.
The mortality rate is quitehigh with it, unfortunately, and
(11:08):
so it's like okay if you'rehealthier and you can kind of
withstand treatment, but we knowthat it's likely a terminal
diagnosis, but we're trying tokind of get as much life
extension as possible.
Perhaps we can go forward withit.
Yeah.
Or your baseline might be prettydeteriorated and adding on more
chemotherapies unlikely goingto really either add much
(11:30):
benefit to to quality of life,it may worsen it, or it may not
extend life out with muchsignificance.
And so perhaps it really isjust about overall, you know,
providing best supportive careand letting them see out the
best of their life.
That's remaining.
Dr. Joshua Goldenberg (11:49):
Yeah, absolutely.
And yeah, advanced pancreaticcancer is not a good one.
We're talking about maybe a fewextra months of survival if
things go well.
Right, I think you know theother thing that you said this
again, but I want to underlinethis is that this was in
addition to sort of standard ofcare, but it's not one of these
(12:10):
integrative studies that we'reused to seeing where you've got
standard of care and then onegroup gets additional
integrative medicine.
It's that or a placebo.
So it's still a placebocontrolled trial, and so we're
basically saying, like, isadding this on any better than
placebo when you already haveall this other stuff on board?
So again, this is not a A plusB versus A.
(12:33):
It's A plus B versus A plusplacebo B.
Dr. Adam Sadowski (12:37):
Right.
And the placebo was exactlyidentical 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 (12:53):
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 toget these adverse reactions and
they did see a dramaticdifference in adverse reaction
between the placebo and misotolduh and that.
But that's a big concern forblinding, for masking, right,
like, yeah, maybe it started offas blind, but you know, it
(13:13):
would be very obvious to tomedical staff and to perhaps the
participants that they know toexpect this if it didn't happen
versus if it did happen.
So we have to think a lot abouteven though it was placebo
controlled.
Did that blind last?
Or was it unmasked during thetrial?
Right, right?
Dr. Adam Sadowski (13:31):
No, I mean, I think it's a good point, but I
mean but which way would thatbias, though?
Dr. Joshua Goldenberg (13:36):
right, like, which way would that bias
that would bias towards benefit,right, because you would know
that you got the mistletoe andso you might expect a better
outcome.
So you know, if this was apositive study, you might say,
oh, maybe we've got an issuethere.
If this was a negative study,then again, it's not just that
it's biased or potentiallybiased, it's the direction of
expected bias.
So, if anything, you wouldexpect this to make things look
(13:57):
rosier.
Dr. Adam Sadowski (13:58):
But if the results are not rosy, then you
don't really have to worry aboutit, because the but overall, if
you have the chance to readthis paper, I actually really
like the way it was outlaid, howit was reported.
I was surprised it was kind ofin this obscure journal.
Right.
It was in a German journal.
(14:18):
Yeah.
But it was very well done.
Yeah.
It was very well done, verywell reported.
Yeah, this was an excellentread.
Dr. Joshua Goldenberg (14:27):
You heard it here Adam likes the study
and it's on integrative medicineand he likes the study but I
agree it was super well done.
I thought but and I wassurprised by the I had the same
thought.
I was like, huh, if it's, youknow, you think of small, like a
randomized, controlled trialresult in a small, or at least I
don't know if it's small, but Ididn't know about this journal,
maybe 30 people or something.
No, this is like a, you know,300 person, randomized,
(14:48):
controlled, conducted.
You know you kind of expectthis in BMJ or something.
Dr. Adam Sadowski (14:53):
Yeah, but yeah, it was a.
It was a double blind,randomized placebo controlled
trial across nine differentoncology centers in Sweden where
people who had a recentdiagnosis of advanced exocrine
pancreatic cancer or a relapseof cancer and they did actually
do analyses where, from asensitivity analysis standpoint,
(15:14):
um, tease that out of like,okay, do the results differ in
people with new diagnosis versusa recurrent?
And, just for sake of time, um,there was no difference when.
When, looking at that and thepeople who entered the trial, um
, they had, from a functionalitystandpoint we're a little bit
on a less severe standpoint theyhave what's called the Eastern
(15:38):
Cooperative Oncology GroupPerformance Status, or the ECOG,
where lower scores indicate ahealthier or more of like a
robust health from a baselinestandpoint.
So if you had an ECOG score ofone, that would be much better
than someone a score of five ismortality.
So if you were, you know, inthis trial they recruited people
(16:01):
with a baseline that was lessthan or equal to two.
So people who, for the most part, are functioning well and if
there's any sort of limitationsthey're not.
They're still able to do liketheir activities of daily living
and whatnot.
They're not like completelydecompensated.
Uh, baseline Um, and theyneeded to have a life expectancy
greater than four weeks.
It makes sense for what they'retrying to find with with this
(16:24):
trial, and then, uh, basicallyjust need them to not be
pregnant, breastfeeding, allsort of like the kind of
standard stuff, not using anysort of other immunomodulating
things, agents, making sure thatno one had, like an autoimmune
disease, anything like that, orbeing treated for an autoimmune
(16:44):
disease.
I didn't really have any sortof issues with the
inclusion-exclusion criteria,did you?
Dr. Joshua Goldenberg (16:51):
No, not at all Pretty.
I didn't really have any sortof issues with the inclusion
exclusion criteria, did you?
No, not at all.
And they they tracked againvery closely with this MAPAC
trial, including for theintervention same intervention,
same dosing, same adaptation ofdosing.
So again they're like thislooks really promising.
Dr. Adam Sadowski (17:05):
Let's see if we can repeat this with blinding
Right People who were alsoexcluded was really anyone who
had a prior experience withmistletoe, or if they had any
sort of known hypersensitivityto mistletoe components.
Makes sense.
Which probably means that theyknew about this skin injection
site reaction.
Dr. Joshua Goldenberg (17:26):
Look, the thing is we don't do this for
money.
This is pro bono and, quitehonestly, the mothership kind of
ekes it out every month or so.
Right, so we do this because wecare about this, we think it's
important, we think thatintegrating evidence-based
medicine and integrativemedicine is essential and there
just aren't other resources outthere the moment.
(17:46):
We find something that does itbetter, we'll probably drop it.
We're busy folks, but right nowthis is what's out there.
Unfortunately, that's it, andso we're going to keep on
fighting that good fight.
And if you believe in that, ifyou believe in intellectual
honesty in the profession andintegrative medicine and being
an integrative provider andbringing that into the
integrative space, please helpus, and you can help us by
(18:08):
becoming a member on Dr JournalClub.
If you're in need of continuingeducation credits, take our
NANSEAC approved courses.
We have ethics courses,pharmacy courses, general
courses.
Interact with us on socialmedia, listen to the podcast,
rate our podcast, tell yourfriends.
These are all ways that you cansort of help support the cause.
(18:31):
Yep, all makes sense.
Got no problem with inclusioncriteria or the intervention or
the design.
Oh, I just want to point outthe design, so statistically.
So they were very careful anddid a good job about intention
to treat analysis right.
So they tracked loss to followup and all that, but they
actually analyzed as per theallocation, which is very, very
important for intention to treatanalysis, especially if there's
(18:53):
differences in continuation oftreatment, which there was here,
which we'll get to in a second.
But yeah, they did everythingkosher from a ITT or intention
to treat analysis perspective.
They did also look at perprotocol and report it
separately in case people wereinterested too.
Dr. Adam Sadowski (19:09):
But they're very clear on their primary
outcome yeah, um, and then whenthey administered, uh, the
mistletoe and the placebo, theybasically titrated them up to
the most, to the highest maximaldose, and then, uh, followed
them up, um, basically on a on amonthly basis up until nine
months, which was the end of thetrial.
(19:32):
And then the primary outcomethat they looked at was overall
survival, and then the secondaryendpoint was health-related
quality of life, and then othersecondary endpoints that I
thought were reasonable wereglucocorticoid use, so, meaning
like, did we have to use anysort of like salvage therapy to
try to get you know kind ofimprove, sort of their function
(19:55):
and and response to to treatmentand the cancer?
They looked at safety outcomesand then they they said that
they were going to look up bodyweight.
I wasn't able to find thoseresults anywhere.
Dr. Joshua Goldenberg (20:07):
They said they're going to publish them
later.
I think Publish them later,Okay.
And then, yeah, they're goingto publish them later.
Dr. Adam Sadowski (20:10):
I think publish them later, okay, and
then?
Dr. Joshua Goldenberg (20:14):
yeah, they're saving their secondaries
for another publication greatum.
Dr. Adam Sadowski (20:19):
And then they , they did um trial, or, excuse
me, they did.
They published not only theirprotocol um prior to this trial
being done, but they alsoregistered registered their
trial in what looked like bothEuropean and US-based registries
, which was really cool yeah.
Dr. Joshua Goldenberg (20:37):
Yep, excellent.
Yeah, they did a great job.
No concerns whatsoever from amethods perspective, besides the
concern for potential blinding,which is not a quality on them,
it's just a manifestation ofthe intervention.
Dr. Adam Sadowski (20:50):
Yep, basically they just needed 290
people in the trial, which iswhat they got, which is pretty
consistent with the prior trial,which needed 220.
So this one had 290, so alittle bit more, but still
consistent with everything.
There were 143 people who werein the mistletoe extract group
and 147 in the placebo group.
(21:11):
Within the mistletoe extract,140 received therapy and in the
placebo group, 143 receivedtherapy.
32 people discontinuedintervention in the mistletoe
group and really the majority ofthat is what I kind of
understood as really just liketreatment fatigue in general,
(21:32):
which is pretty pragmatic oflike people just saying, hey,
you know what, I think I'm donewith treatment and just kind of
want to live out the rest of mylife.
Dr. Joshua Goldenberg (21:40):
Hmm, I had a different take on that,
because if you look at the otherside placebo, you only had 18
people discontinued versus youalmost have double that.
Dr. Adam Sadowski (21:49):
I thought it was because of the reactions but
they did discontinue yeah, buttwice as many people they did
discontinue for basically thesame reason, though right.
Dr. Joshua Goldenberg (21:58):
So like that's the like, that's the
question.
So I think it was, I think itmight have been the reaction.
They didn't like the reaction,the localized reaction I'm
trying to look here it might beme reading between the lines
here, but there was a dramaticdifference in the skin reaction.
So like 93 out of 140 peoplewho got the actual mistletoe had
these skin reactions, versuslike two people in the placebo
(22:21):
group.
Dr. Adam Sadowski (22:22):
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 thatwas for all the people who did
not, who ultimately decided notto enter the trial, or they
combined the two, so they didn'tactually hash that out.
So you might be right there.
(22:42):
So that's a good point.
Dr. Joshua Goldenberg (22:45):
Well, I guess the reason I'm harping on
it is like, if you have animbalance and the reason for the
imbalance is related to theintervention or the outcome, you
have a potential bias issue andthe concern is this may be
related to the interventionbecause it causes these, you
know these reactions.
Again, however, this would be amajor concern if you did like a
(23:05):
per protocol analysis orsomething like that they did,
analyzed as as allocated, sothat was all good.
And again, the direction ofthis concern that I have would
be to make things look rosierthan they are, and if we don't
see a rosy result, it's sort ofa non-issue, but that's why I'm
kind of harping on it.
It's like we do see thisdoubling of dropouts and I think
(23:26):
you can make an argument thatthe dropouts have to do with the
intervention.
It's not necessarily random.
Dr. Adam Sadowski (23:33):
And we do also see that, you know, when,
looking at both intention totreat and per protocol analysis,
the results were essentiallypreserved.
Dr. Joshua Goldenberg (23:40):
Yeah, that was cool.
It's nice to also report perprotocol, but just not harp on
it, which is exactly what theydid.
They put it in an e-supplement,but they said that basically
the results were the same.
So, even with all theseconcerns, again, Yep and then at
baseline.
Dr. Adam Sadowski (23:58):
For the most part, the characteristics of
participants was pretty wellbalanced, with the exception of
a couple of changes here andthere with regards to where
people's cancer staging was atand whether or not they had a
new diagnosis or if it was arelapse even did like, didn't
they do like a sensitivityanalysis later and said, no,
(24:20):
that that won't impact theresults either.
Dr. Joshua Goldenberg (24:22):
Right, even though there are.
Yeah, so that's common.
Like if you do, you know yourandomize people, but just by
random chance sometimes thegroups look different and you
want to make sure that theresults that you see are not
because of that difference.
So they did that as asensitivity analysis and they
did not see a signal thereeither.
Dr. Adam Sadowski (24:40):
Yeah, I think they did four sensitivity
analyses, um, looking atdifferent things, um, and they
just didn't find any reallychanges in the results, which is
again uh, which is good fromlike the consistency standpoint
and like how, how, how much canwe believe in these results?
Dr. Joshua Goldenberg (24:54):
so, yeah, okay, totally agree, love it,
loving.
So far, they did a reallyamazing job.
Dr. Adam Sadowski (25:02):
Yeah, so when we look at the primary outcome,
which was again overallsurvival compared to placebo, we
saw that there was no, therewas no difference.
Yeah.
The adjusted hazard intervalwas a 0.89 to a 1.44.
(25:22):
And yeah it just.
It just did not change.
Dr. Joshua Goldenberg (25:27):
Yeah, it's a shame.
And then, yeah, they did allthe sensitivities about the same
.
Yeah.
Dr. Adam Sadowski (25:32):
And actually from like a nominal standpoint.
The median overall survival was7.8 months in the mesothelial
group versus 8.3 in the placeboarm.
Dr. Joshua Goldenberg (25:42):
Right, so nominally, uh, even a little
bit worse, but not statisticallysignificantly different.
Yeah.
Dr. Adam Sadowski (25:48):
Yeah, exactly Uh.
There was also no change uh inthe health related quality of
life compared to to to eithergroup Um, and they had uh 99, 99
percent uh questionnairecompletion rate.
Dr. Joshua Goldenberg (26:01):
so yeah, and no loss to follow-up man.
They had no loss to follow as awell-conducted study there's no
, no loss of data there.
Dr. Adam Sadowski (26:09):
I mean, if you look at figure two as well,
uh, when they look at overallsurvival, um, from start of
treatment to treatment period,to excuse me, end, end of the
treatment period, so from fromwhen they entered the trial
until month nine, just lookingat that, basically the lines are
(26:32):
right on top of each other.
There's no, there's nodivergence, um, and then they
said, okay, well, what if we doit for the entire follow-up
period as well, after, after thethe treatment was administered?
And again we see no divergenceat all.
They're just basically on topof each other the entire time
yep, yep, that's totally true.
Dr. Joshua Goldenberg (26:48):
So it's like, okay, well, maybe, maybe
the effects, uh, you know youneed longer to see the effects
and yeah, up to what, uh, fouryears later, right?
Dr. Adam Sadowski (26:57):
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 thediscussion section.
Dr. Joshua Goldenberg (27:07):
I did read it just to kind of see what
see if they would compare theresults to the.
Dr. Adam Sadowski (27:11):
You must have really liked the paper I did,
and I wanted to see what likehow they compare it to the MAPAC
trial.
I thought that they were veryneutral in their tone as to how
they compared to the MAPAC trial.
Mm, hmm.
Dr. Joshua Goldenberg (27:23):
Agree, yeah, they again.
They just really.
And they had some, you know,thoughtful analysis, which is
what you're supposed to do, orthoughtful discussion, which is
what you're supposed to do inthis discussion, like, why did
it work in that trial but notthis one?
So they talked about blindingis the obvious one, but they
said you know differencesbetween uh serbia and uh.
you said sweden, right yep um,and I thought that was
(27:44):
interesting, that they um, Imight be stealing your thunder
here, but that there might havebeen like a ceiling effect.
So like in uh serve, let me seeif I get this right, it's
serbia, they said.
There's not as much, it's nothaving this sort of a great care
and um, end of life additionalcare is not common, and so there
might have been additionalbenefits to glean from something
(28:06):
like mistletoe, but that inSweden it's very standardized to
do all these advanced sort ofend of life, advanced pancreatic
cancer care, and so you mighthave already got all the benefit
you could get from additionalinterventions and you sort of
had that ceiling effect and themistletoe was not able to add
anything to that, which is alsouseful information.
(28:26):
But so they conjectured alittle bit on that.
I thought that was that wasinteresting.
I wouldn't.
I don't think I would havethought of that on my own.
Dr. Adam Sadowski (28:34):
Yeah, yeah, sometimes you know, when we read
negative trials or quote,unquote negative, they're
reported as negative because theresults are not statistically
significant.
So people kind of view them aslike, oh well, this doesn't
really add to science.
I really think the completeopposite, especially if it's
something that's really wellconducted, of like there was no
bias really going into thispaper.
(28:55):
If anything, it was kind ofmistletoe leaning.
If anything, it was kind ofmistletoe leaning and they were
like, hey, we were actually kindof surprised with the results
that we got, given just howrobust the findings were in the
mapac trial totally and likeit's just, it's just an
unfortunate finding.
like they, they did a reallygood job, they got the product
from the correct industry, theyused a multidisciplinary team,
(29:19):
they did every, they dideverything right, like as much
as you could, and so, yeah,there's just nothing there.
Yeah, there's nothing there.
You know, if we were to do agrade on this it would be high,
right, we would probably have ahigh grade score and unlikely to
change, you know, outcomesmoving forward, at least when it
(29:40):
comes to advanced pancreaticcancer.
Now we can't say, well, thisapplied to, you know, breast
cancer, colon cancer, any othertypes of cancer.
We can really only say hey, inin a European patient population
, you know, in a, at least inSweden, if we're looking
strictly at this.
But now we have Sweden in oneof the one of the you know
(30:01):
Baltic states, that there thereseems to be a, at least in
Sweden, if we're lookingstrictly at this.
But now we have Sweden in oneof the one of the you know
Baltic States, that there thereseems to be a conflicting
evidence.
But the higher level ofevidence is pointing towards a
null effect.
And uh, you know I wouldcaution, based on these results,
that perhaps you don't utilizethis now if you are seeking it.
Yeah.
(30:22):
I don't know the authors did areseeking it.
Yeah, I don't know.
The authors did talk about thatin the discussion of like hey,
you know, people may be maybewanting to use this and you know
, you just have to kind of likelet them know yeah, yeah, I
think that's fair I think.
I think what they reported waswe know it's, it's, it's at
least safe that it doesn'tinteract with the chemotherapy
yeah, that's true.
We didn't talk about that,that's true and that safety was
(30:45):
really limited to theseinjection site reaction, these
localized injection sitereactions which were minor but
otherwise we did not see anysort of significant harms.
And if they are still adamanton wanting to use this, based on
this data and and they do showthe different types of
chemotherapy regimens that wereused that at least over this
timeframe it appeared to be safe.
(31:07):
However, we also know thatclinical trials suck at
reporting safety data.
Dr. Joshua Goldenberg (31:11):
Yeah, that's true, rare safety data in
particular, and so I don't know, I would take issue with, I
think, the thought, yourstatement that maybe lean away
from it.
Just because, at the end of theday, we've got two trials, two
randomized trials they're nothuge, about 200, 300 people each
the grade level, just fromprecision, because of the small
(31:33):
size, would be low.
You'd probably rank down onceor twice just for that.
And one of the studies was highrisk of bias.
So you know, I think still,even though this was a great
study, still the grade levelwould probably be low for this
result just because of theoverall size.
And you know it could be that.
You know it could be nullbecause of bias.
(31:54):
That was in the initial trialand this was addressed.
That it could be null because,hey, randomness and that's why
we do meta-analyses could bedifferent because of the patient
populations, like theyconjectured about access to
palliative care.
So these are all really goodquestions, but I think, at the
end of the day, you now have avery good study conducted in a
(32:15):
high resource available countrythat unfortunately did not see a
signal at all with thisintervention for advanced
pancreatic cancer, despitepromising previous results.
Dr. Adam Sadowski (32:28):
And based on the language you used in this
paper, a country and medicalsystem.
That is like kind of I don'tknow a caution to say in favor
of, but accepting of of thisintervention and like, again,
everything was set up to likehave this work and it didn't.
Dr. Joshua Goldenberg (32:48):
That's right.
I think that's true.
I got that same take.
It's like, oh, these peoplereally thought this was going to
work and they wanted to do itmore 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 otherdirection, like one of those
studies like we're just going toprove that this herb doesn't
work, type of thing.
I did not get that sense at allno, no, no.
Dr. Adam Sadowski (33:06):
I think sometimes when you read the
introductions of paper, you kindof like you can tell know where
it's going.
I'm like, all right, yeah, likethis was this is going to be a
negative trial, and they'regoing to set it up that way.
And, yep, there are the resultsand it's a negative trial.
And, oh, look at the conclusionYep, yep, nope, yep, they did
not want this to work.
This was the opposite.
They're like, hey, no, thismight work, like we need to
study this.
There's a lot of, there'sseveral meta-analyses looking at
(33:28):
it and everything is like thequality of data is just not
there.
Dr. Joshua Goldenberg (33:32):
We're going to make some high quality
data data and unfortunately, youdon't like the way that the
cake tastes.
Yeah, yeah, no, that could betrue.
And then another interestingthing I find this idea of like
why studies have divergentresults fascinating.
One argument that I've seen forwhy the more we study something
(33:53):
, the less impressive it looks,is that you shift the population
that you study, right.
So sometimes you'll study themost severe cases first because
there's no other option outthere for them, and then you say
, oh, it works for that, let'stry it for moderate, let's try
it for mild, and maybe it's justnot 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
(34:13):
similar, if not identical, tothe previous trial that really
was set up to ask the samequestion 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, besidesjust it being randomly different
.
Right, right, right, right.
Dr. Adam Sadowski (34:32):
Awesome.
Dr. Joshua Goldenberg (34:33):
All right , ladies and gentlemen, that's
what we have to say formistletoe today.
Thank you, dr Jacob Shore, forthat great recommendation.
You impressed, adam, and that'shard to do.
All right, we'll talk to youlater.
Bye, everybody.
If you enjoy this podcast,chances are that one of your
colleagues and friends probablywould as well.
(34:54):
Please do us a favor and letthem know about the podcast and,
if you have a little bit ofextra time, even just a few
seconds, if you could rate usand review us on Apple Podcast
or any other distributor, itwould be greatly appreciated.
It would mean a lot to us andhelp get the word out to other
people that would really enjoyour content.
Thank you, hey y'all.
This is Josh.
You know we talked about somereally interesting stuff today.
(35:14):
I think one of the things we'regoing to do that's relevant.
There is a course we have on DrJournal Club called the EBM
Boot Camp.
That's really meant forclinicians to sort of help them
understand how to criticallyevaluate the literature, etc.
Etc.
Some of the things that we'vebeen talking about today.
Go ahead and check out the shownotes link.
We're going to link to itdirectly.
I think it might be of interest.
(35:35):
Don't forget to follow us onsocial and interact with us on
social media at drjournalclubdrjournalclub on Twitter, we're
on Facebook, we're on LinkedIn,etc.
Etc.
So please reach out to us.
We always love to talk to ourfans and our listeners.
If you have any specificquestions you'd like to ask us
about research, evidence, beinga clinician, etc.
(35:55):
Don't hesitate to ask.
And then, of course, if youhave any topics that you'd like
us to cover on the pod, pleaselet us know as well.
Introducer (36:05):
Thank you for listening to the Doctor Journal
Club podcast, the show that goesunder the hood of
evidence-based integrativemedicine.
We review recent researcharticles, interview
evidence-based medicine thoughtleaders and discuss the
challenges and opportunities ofintegrating evidence-based and
integrative medicine.
Be sure to visitwwwdocorjournalclubcom to learn
(36:28):
more.
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