Coffee and Pancreatic Cancer
An Interview With Brian MacMahon
On March 12, 1981, the New
England Journal of Medicine published a case-control study
reporting a strong association between coffee consumption and
pancreatic cancer. The principal investigator was Brian MacMahon
and co-investigators included Stella Yen, Dimitrios Trichopoulos,
Kenneth Warren and George Nardi, all from the Harvard School of
Public Health. The association was not diminished by controlling
for cigarette use, and for the sexes combined, there was a
significant dose response relation. The relative risk associated
with drinking up to two cups of coffee per day was 1.8 (95% C.L.
1.0 - 3.0) and that with three or more cups per day was 2.7 (1.6 -
4.7). The authors were guarded in their conclusion-- ď...The
positive association with coffee consumption that we observed must
be evaluated with other data before serious consideration is given
to the possibility of a causal relation.Ē
Their findings, if confirmed, would have considerable public
health implications. Cancer of the pancreas is the fourth most
common fatal malignant disease in the United States and accounts
for approximately 20,000 deaths annually. The implications were
made clear by the authors themselves when they estimated that as
much as 50% of pancreatic cancer is potentially attributable to
coffee consumption. An account of the study was published in the
New York Times on the same day, and the report received wide
spread publicity throughout the country. The study was criticized
by the National Coffee Association and by epidemiologists in a
subsequent story in Medical World News (MWN), much of it focusing
on the appropriateness of the hospital control group. The New York
Times editorial page pronounced it fit to believe because it had
the Harvard University and New England Journal of Medicine seal of
approval according to the MWN story.
The Epi Monitor contacted Dr. MacMahon and he willingly agreed to
discuss the study and subsequent developments surrounding its
publication. Following is the text of our interview.
Epi Monitor: In light of the comments that I have been made
by other epidemiologists and the reactions you have received since
publication of your report, what are your current feelings about
the appropriateness of your control group?
satisfied with it. I think that there was one point about it that
we missed. We were concerned to show that the pancreatic cancer
cases differed both from the cancer controls and the patients with
non-malignant disease. What has been pointed out subsequently is
the possibly heavy weighting of the control group with patients
with gastrointestinal disorders. I think that if that point had
occurred to me before publication I would have added information
showing that the relationship holds whether you exclude
gastrointestinal disorders or not, although it is true that the
relative risks are reduced by excluding the patients with
Moreover, you have to consider that cancer of the pancreas starts
also with gastrointestinal symptoms, and itís an open question as
to whether or not you should exclude the patients with
gastrointestinal disorders; maybe the control group with the GI
diseases included is better than the one without them in the sense
of being more similar to the pancreas cases. Also, donít forget
that the question we asked related to coffee drinking prior to
onset of this illness, the illness for which the patient was
hospitalized. I think thereís a question there and thereís a
question in peopleís mind, but Iím satisfied that weíve taken care
Epi Monitor: There
were some questions which you raised yourself in the paper about
the control group.
MacMahon: As you know
in an observational study there is never a perfect control group,
and while we do plan in a study which I may tell you about later
to include a general population control group, I donít think that
is going to be perfect either. You will always have a high rate of
refusal in a randomly sampled general population control group and
the circumstances of the interview are not the same as when you
are interviewing in hospitals. I think there are things to be said
pro and con for a variety of controls.
Epi Monitor: What are
your comments about the differing results that youíve observed in
males and females? Some people were skeptical because there was no
dose response effect in the male group.
MacMahon: That could
readily be due to chance. If one value in the male data were
changed to another value well within the confidence limits of that
rate ratio, we would have a nice dose relationship in males too.
Epi Monitor: In all the things that youíve heard since the study
was published, is there any other supporting evidence that people
have brought to your attention or any other evidence which tends
to make the association less likely?
MacMahon: The authors
of three Letters to the Editor of the NEJM have kindly sent me
copies. There are three sets of data--all relatively small, and I
donít think I should describe their findings until they are
published, except to say perhaps of the three sets I have seen,
one is supportive and two find no relationship.
Epi Monitor: These represent direct evidence on the association
between coffee and pancreatic cancer. What about other indirect
evidence --such as the low pancreatic cancer rates in Mormons--has
any of that surfaced that tends to support or take away from the
Epi Monitor: In light
of fairly guarded statements in your paper about this association,
what were your reactions to the criticisms? Were they justified?
MacMahon: I havenít
had much criticism. Iíve seen at least one abusive piece in the
newspaper which was just taking off at us, and I have had letters
saying--Why donít you stay at home and treat people or help them
get better instead of taking away our coffee--but I donít consider
that as criticism. Iíve had some questions such as the one on the
control group put to me but again, not in any critical way.
Epi Monitor: Have you
seen the piece in Medical World News?
MacMahon: No, I
Epi Monitor: The
headline reads ďStorm Brews Over Study Tying Coffee to Pancreatic
CancerĒ and features criticisms from Alvin Feinstein, David Rush,
and Irving Kessler.
MacMahon: I had a
call from David Rush. I didnít take the call, but I got the
message. I didnít know what he was referring to. He said that he
felt his remarks had not been properly interpreted in the paper
and I did not know which paper he was talking about. He must have
been talking about that one.
Epi Monitor: If you
have not received muchcriticism, your report certainly received
much attention and publicity. What was it like?
MacMahon: It was just
impossible to take all the calls. It has died down now, but four
or five calls were coming in at a time. It is an interesting
experience. The first copies of the NEJM were received on a Monday
or Tuesday. On Monday afternoon and Tuesday, I got calls from some
of the better known journals. These people obviously read the
article and they had intelligent questions to ask. It was no
problem to deal with that. By Wednesday the word had gotten out in
some fashion, maybe on a network, to lots of small radio stations
and newspapers all over the country. They had not seen the article
and they said please tell us what you did and what you found. By
the time youíve done that a 100 times in a day, youíre a bit sick
of it. So there was the physical impossibility of answering all
the calls, and next, I got to the point where I decided I just
couldnít live my life for that. I gave the thing five days and
after that I quit.
Epi Monitor: Was the
reaction and publicity unexpected?
MacMahon: I expected
some reaction but not anything of this strength.
Epi Monitor: Why do
you think your report received this much publicity?
MacMahon: I think it
was a combination of them not having anything else to do that day,
the fact that it is coffee--itís almost like apple pie as
Americans go--and it gives some of them an opportunity to have a
go at the mad scientists who are always finding things that cause
Epi Monitor: What
advice would you give to other epidemiologists who are confronted
with the possibility of the same kind of publicity?
MacMahon: I would
publish it on the day that the President gets shot or some other
thing that keeps these people busy.
Epi Monitor: Do you
think that in the end the publicity was a good or bad thing?
MacMahon: It depends
on whether itís right or not. If it turns out to be right--that
the association is there--then I think it will be a good thing.
Weíre having all kinds of difficulty with the bureaucracy that has
grown up around human subject committees. I think that a
demonstration to the public that from time to time this kind of
research does turn up a useful thing will all be to the good. If
it turns out that the association is not present--that something
is wrong with our data--then, of course, it will be a bad thing
because it will tend to discredit the method.
Epi Monitor: There is
a fair amount of cynicism in society now because it seems like
whenever we read the newspapers we are learning about some other
thing that we should or should not do. Do you think that this is a
problem today in terms of the reputation of epidemiology? Do you
think that in the end if weíre not careful about the validity of
associations that we publish, that we will make our work more
difficult in the long run?
MacMahon: Yes, I
think we should be very careful about publishing data like that,
especially data that are likely to be inflammatory.
Epi Monitor: Did you
think about that at all before publishing your report?
MacMahon: Iíve been
sitting on this for two years thinking about it. But it is 369
cases, the largest series by far that has been published. It is a
strong association and you have an obligation to get out what
appear to be meaningful associations. You have that obligation as
well as the obligation to be careful of what you do. You have to
find the line somewhere in between. I think that on a data set
this size, with the findings that we had, there was an obligation
to get it out.
Epi Monitor: Is the
fact that you were concerned to some extent about the reputation
or credibility of epidemiology in general one of the
considerations that made you wait so long before publishing it?
MacMahon: Yes. And
concerned about my own reputation also.
Epi Monitor: The New
York Times reported that you have stopped drinking coffee, but
that you would not presume to advise others. What were some of the
factors that entered into your decision to quit?
MacMahon: Well, it
was in part real in the sense that it was based on my assessment
of the likelihood that this association was going to turn out to
be real. Itís also in part to produce a public image that is
consistent. I wouldnít be concerned at all about my epidemiology
colleagues who understand the nature of the data and the attending
uncertainties. I wouldnít be concerned at all about consistency
with them. I can very well see an epidemiologist looking at this
set of data, deciding for the moment that he or she is going to
continue drinking coffee, but that isnít how the general public
and the press want it. They want black and white answers--is it or
isnít it? If you force yourself to a black and white answer, Iím
still of the opinion that this is more likely black than white. If
the press forces you to that kind of answer-- which they do when
they ask you what do you do--you canít say that I really believe
this but on the other hand I am going to continue drinking coffee
myself. That I think is an insult to the data and to the study.
Epi Monitor: One
final point would be your own plans for the future. Do you have
plans for additional studies and could you outline in some detail
that epidemiologists would appreciate where you go from here?
hoping to begin a new case control study with the same kind of
methodology but with two additions. The question will be focused
more on coffee, trying to get some estimate of lifetime
consumption as well as what kind of coffee is most usually used,
whether itís dried or percolated, decaffeinated or not, and what
additives are used. The second major change would be to
incorporate a general population control group.
Epi Monitor: Are you going to do two case control studies?
MacMahon: No, one
study with two control groups.
Epi Monitor: Would it
be with a new case series?
Epi Monitor: Also in
the Boston area?
MacMahon: Yes, 10
hospitals, using hospitalized cases, hospitalized controls, and
general population controls.
Epi Monitor: What
length of time do you think this would involve?
MacMahon: Four years.
Epi Monitor: Are
there any other things you would like to say or comment on that
havenít been raised or that you think other epidemiologists would
MacMahon: I think
that itís important to say that the great majority of the letters
I received were trying to be helpful and some of them were indeed
very helpful. They included very detailed accounts from people in
the coffee industry who really wanted me to be educated about what
a complex substance coffee is, some very interesting case reports,
and concerned letters from people with families and friends that
they have been worrying about.
Epi Monitor: How many
letters have you received?
MacMahon: I havenít
counted them, but it must be two or three hundred.
Epi Monitor: And
these have come from all over the world?
Epi Monitor: Have you
ever had this kind of attention from anything else youíve ever