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Historical Interviews
Coffee and Pancreatic
Cancer
In 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-- “...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.”
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?
MacMahon: I’m
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 gastrointestinal disorders.
Moreover, you have to consider
that cancer of the pancreas starts also with gastrointestinal
symptoms, and it’s 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, don’t 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 there’s a question there and there’s
a question in people’s mind, but I’m satisfied that we’ve taken care
of that.
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 don’t 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 you’ve
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 you’ve 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
don’t 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 association?
MacMahon: No.
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
haven’t had much criticism. I’ve seen at least one abusive piece in
the newspaper which was just taking off at us, and I have had letters
saying--Why don’t you stay at home and treat people or help them get
better instead of taking away our coffee--but I don’t consider that as
criticism. I’ve 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
haven’t.
Epi Monitor:
The headline reads “Storm Brews Over Study Tying Coffee to Pancreatic
Cancer” and features criticisms from Alvin Feinstein,
David Rush, and Irving Kessler.
MacMahon: I had
a call from David Rush. I didn’t take the call, but I got the message.
I didn’t 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 you’ve done that a 100
times in a day, you’re 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 couldn’t 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--it’s 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 cancer.
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 it’s right or not. If it turns out to be
right--that the association is there--then I think it will be a good
thing. We’re 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 we’re 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: I’ve
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.
It’s also in part to produce a public image that is consistent. I
wouldn’t be concerned at all about my epidemiology colleagues who
understand the nature of the data and the attending uncertainties. I
wouldn’t 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 isn’t how the general public and the press want it. They want
black and white answers--is it or isn’t it? If you force yourself to a
black and white answer, I’m 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 can’t 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?
MacMahon: We’re
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 it’s 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?
MacMahon: Yes.
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
haven’t been raised or that you think other epidemiologists would find
interesting?
MacMahon: I
think that it’s 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
haven’t counted them, but it must be two or three hundred.
Epi Monitor:
And these have come from all over the world?
MacMahon: Yes.
Epi Monitor:
Have you ever had this kind of attention from anything else you’ve
ever done before?
MacMahon: No.
Published April/May
1981
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