Risk of ovarian cancer in women with symptoms in primary care: population based case-control study

Hamilton et al's response to criticism of their paper is welcome, if
belated.

The authors continue to promote certain symptoms as effective
predictors of
ovarian cancer, although their acceptance now that these features are in
fact
of "low risk" of being useful is also welcome. Despite the authors'
enthusiasm,
their study has significant problems of retrospectiveness and lack of
precision
in defining symptoms (for example, when does "abdominal bloating" become
"abdominal distention"?) There are other significant problems described
previously in rapid responses, for example the (typically) six week period

between referral and diagnosis which, if removed from the right side of
the
authors' charts then much of the increase if symptom frequency disappears
too.

The central point they miss about the high community prevalence of
such
symptoms is that in widely publicising their study they have actively
encouraged women experiencing these symptoms to present for
investigation, when the predictive value of these symptoms is far from
certain.

But perhaps the most breathtakingly audacious claim by the authors is
that
the media reports of their findings were apparently none of their
responsibility. However, it is quite clear that they quite deliberately
arranged
to speak to the national non-medical media, who quoted them claiming that
a variety of early symptoms should suggest ovarian cancer when their paper

provided no evidence at all to support this. For example, in The Times
they
were quoted as saying:

“Many of the symptoms described by women ... include fatigue,
abdominal
pain or subtle changes in urination or the bowels. With those, quite
simply
ovarian cancer doesn’t spring to the GP’s mind. Unquestionably, some women

have their cancer missed and have to return, sometimes repeatedly. Ovarian

cancer is not a ‘silent killer’ — it is just not being heard.”

In The Telegraph they are quoted as follows: "quite simply ovarian
cancer
doesn't spring to the GP's mind. Does that make it late diagnosis, missed
diagnosis, or difficult diagnosis? What it does mean is that there is
potential
for improvement. Unquestionably some women have their cancer missed and
have to return - sometimes repeatedly.”

Despite this, they make the remarkable claim that such media reports
were
"unprompted by us". Either the quotes are accurate, in which case they go
far
beyond the limited findings in their paper, or they are not accurate, in
which
case the authors have a responsibility to publicly disown them and take
steps
to correct them. They say that "journalism will always be like this, often

preferring emotive reportage to balanced coverage." Yet in fact it
appeared to
be the authors themselves who provided the emotive and inaccurate
statements associated with wide media reportage, which appeared to be an
end in itself.

I would welcome a further explanation from the authors as to their
role in the
widespread inaccuracies in the reportage.

Competing interests:
None declared

Dr Hamilton and colleagues(1) present the results of their excellent
study of symptoms in women with ovarian cancer in terms of “positive
predictive values”. Whilst these have intuitive appeal, some care is
needed in their interpretation when used in the context of symptoms.

The usual formula for positive predictive value (PPV) uses the
prevalence of disease. In this context, one would want the prevalence of
undiagnosed ovarian cancer. The authors use one year’s incidence instead.
Thus, strictly speaking they are estimating the probability that a woman
with particular symptoms will be diagnosed with ovarian cancer over the
next 12 months. This may be a reasonable surrogate for having undiagnosed
ovarian cancer at the time given that the prevalence of ovarian cancer on
first screen tends to be somewhat greater than one year’s incidence(2).
Moreover, it is particularly appropriate that the authors used the same
time period of 12 months for incidence and symptom data in the PPV
calculations.

A bigger concern is the suggestion that the predictive values refer
to women not already under investigation for ovarian cancer. Our own as
yet unpublished data suggest that women in the UK take a median of 1.6
months (interquartile range 1.1, 5.0) to get from first GP referral to
ovarian cancer diagnosis (AWW Lim [PhD Thesis], University of London,
2009, unpublished data). Thus, it seems likely that within a month of
diagnosis, any symptom that appears will be in a woman who is already
being investigated (for an earlier symptom). If one were to exclude
symptoms within 30 days of diagnosis, the data presented in the authors'
Figure 1, indicate that the positive predictive value for abdominal
distension could be between a third and a half of the 2.5% cited in the
paper.

1. Hamilton W, Peters TJ, Bankhead C, Sharp D, Hamilton W, Peters TJ,
et al. Risk of ovarian cancer in women with symptoms in primary care:
population based case-control study.[see comment]. Bmj 2009;339:b2998.

2. Menon U, Gentry-Maharaj A, Hallett R, Ryan A, Burnell M, Sharma A,
et al. Sensitivity and specificity of multimodal and ultrasound screening
for ovarian cancer, and stage distribution of detected cancers: results of
the prevalence screen of the UK Collaborative Trial of Ovarian Cancer
Screening (UKCTOCS). Lancet Oncol 2009.

Competing interests:
None declared

Dear Editor,

With great interest we read a primary care based case-control study
on the value of symptoms in diagnosing ovarian cancer in primary care [1].

Although the title of the article is compelling, we found it confusing and
premature as well and we would like to make a few comments on the
conclusions of this study.

Although the authors detected significant associations between symptoms of
bloating and increased abdominal distension with the diagnosis of ovarian
cancer, these associations do not mean that these symptoms are early signs
of ovarian cancer. Once ovarian cancer causes abdominal distension this is
usually due to a large ovary, omental cake and/or ascites. These are
symptoms of an advanced stage disease and visiting a doctor at that time
will result in the diagnosis, but not improve prognosis. Another comment
we would like to make is that symptoms of bloating and abdominal
distension are very a-specific signs. Almost every woman knows them as a
frequent complaint in the second half of the menstrual cycle. Also women
with irritable bowel syndrome (IBS) experience these symptoms very
frequently if not daily. As most women will not visit their GP due to
these symptoms, this study can not be considered as a population based
study. And last, but surely not least, giving much attention to these a-
specific signs and advising women to see a gynaecologist for
ultrasonography is most likely not cost effective and will cause a lot of
anxiety and cancer worries. Based on the presented results it can be
estimated that a symptom such as abdominal distension will yield
additional 14 referrals per year for each GP and a symptom such as
abdominal pain will give additional 217 referrals per year for each GP.
Whether these referrals will result in earlier diagnosis of ovarian cancer
has not been proven with this study. Only a prospective trial will do.

We have more than 15 years of experience in ovarian cancer screening in a
high risk population. Even in this high risk population with an annual
gynaecological screening and the possibility to come earlier once there
are symptoms, we were only able to diagnose ovarian cancers in an advanced
stage (IIIC) [2]. Therefore, instead of putting great effort, workload and
money in late and a-specific signs and symptoms without proven efficacy in
reducing mortality from ovarian cancer, we would like to recommend putting
more effort in research on biomarkers to detect ovarian cancer in an early
stage.

Prof. MJ Mourits, PhD, MD (1), GH de Bock, PhD (2)

Departments of Gynaecologic Oncology (1) and Epidemiology
(2)University Medical Center Groningen, University of Groningen,
Groningen, The Netherlands

References:

1. Hamilton W, Peters TJ, Bankhead C, Sharp D. Risk of ovarian cancer in
women with symptoms in primary care: population based case-control study.
BMJ 2009; 339:b2998.

2. Van der Velde NM, Mourits MJE, Arts HJG, De Vries J, Leegte LK,
Dijkhuis G, Oosterwijk JC, De Bock GH. Time to stop ovarian cancer
screening in BRCA1 and BRCA2 mutation carriers? Int J Cancer 2009; 124:
919-23.

Competing interests:
None declared

Thanks to Rosemary Tate - the difference between the prevalence of
abdominal bloating in community surveys and that recorded in medical
record computer databases is exactly the point made in my response.

Computerised medical records are great for performing searches, but
no-one
would claim that everything in the consultation will be recorded verbatim,
or
even comprehensively - recording is selective. Patients may not reveal the

abdominal bloating they may have, and if they do it may not be recorded if

not thought to be a key element of the consultation by the highly time-
pressured GP.

Several points come through from some of the excellent responses
above.

The authors in the paper effectively claim that the clinical feature
of
abdominal distension is being ignored by GPs and that this leads to
delayed
diagnosis of ovarian cancer. However, what patients and GPs meant by
abdominal distension is never defined, and importantly there is little
sense of
how, when used by patients and GPs, this symptom differs from abdominal
bloating, a much more common symptom and one with little or no predictive
value. Further work is needed to define what the patients and GPs meant by

"distension" as opposed to "bloating", before there can be any credible
claim
of use of this symptom as an effective way of predicting who should go on
to
further investigation.

As pointed out above, one of the problems with the retrospective
design of
this study is that, when those unfortunate enough to develop cancer look
back, their early symptoms of disease may be obvious to them, but in fact
these same symptoms may have been experienced by those without cancer to
more or less a similar degree. Their significance is obvious to the
sufferers
only because, quite understandably, they focus down on to their own
subsequent experience.

Finally, the limited new findings from this paper make the various
claims of
Hamilton to the non-medical media after publication of his paper all the
more surprising, particularly when he refers to clinical features
supposedly
"missed" when he has failed to put forward credible evidence that they
have
any worthwhile predictive value at all.

For example, to The Times ("Women with ovarian cancer ‘dying because
GPs
fail to spot signs’ " 26 Aug), he states: “Many of the symptoms described
by
women ... include fatigue, abdominal pain or subtle changes in urination
or
the bowels. With those, quite simply ovarian cancer doesn’t spring to the
GP’s
mind. Unquestionably, some women have their cancer missed and have to
return, sometimes repeatedly. Ovarian cancer is not a ‘silent killer’ — it
is just
not being heard.”

in The Telegraph ("Ovarian cancer patients face delays 'because
symptoms go
unrecognised' " 25 Aug), he opines that: "quite simply ovarian cancer
doesn't
spring to the GP's mind. Does that make it late diagnosis, missed
diagnosis,
or difficult diagnosis? What it does mean is that there is potential for
improvement. Unquestionably some women have their cancer missed and
have to return - sometimes repeatedly.”

I'm sure Hamilton is aware that of his obligation to, when
"presenting your
research findings to the non-medical press you should make every effort to

ensure that your research findings are reported in a balanced way." On the

face of it, it's difficult to see how Hamilton can square his extensive
media
claims prompted by his paper with the findings of the study itself, and
his
obligation to comment on them responsibly.

Competing interests:
None declared