NICE guidance on ovarian cancer diagnosis

NICE, in new guidance, are telling GPs to perform CA-125 tumour markers in patients with possible ovarian cancer. They say

“Asking the right question – first tests
Measure serum CA125 in primary care in women with symptoms that suggest ovarian cancer (see section 2.1 on page 43).
If serum CA125 is 35 IU/ml or greater, arrange an ultrasound scan of the abdomen and pelvis.
If the ultrasound suggests ovarian cancer, refer the woman urgently for further investigation
For any woman who has normal serum CA125 (less than 35 IU/ml), or CA125 of 35 IU/ml or greater but a normal ultrasound assess her carefully for other clinical causes of her symptoms and investigate if appropriate if no other clinical cause is apparent, advise her to return to her GP if her symptoms become more frequent and/or persistent.”
But there are several problems.
The symptoms NICE list as potential for ovarian cancer are here:
“persistent abdominal distension (women often refer to this as „bloating‟)
feeling full (early satiety) and/or loss of appetite
pelvic or abdominal pain
increased urinary urgency and/or frequency.”
These are quite common symptoms, and while ovarian cancer is certainly on the list of diagnosis, so are many other things: the tests I would do in a clinical situation would not just be to exclude or to diagnose ovarian cancer.
So when NICE say that CA-125 (a blood test) has to be done first, and an ultrasound only if the result is high, I don’t think they are reflecting the context of a usual consultation. An ultrasound would be high on my list of investigations, because it will be able to give information about other abdominal organs, not just the ovaries. After all, most women with these symptoms will not have ovarian cancer. NICE say that only 0.23% of women with these symptoms will have ovarian cancer.
NICE seem to suggest that a CA-125 being low can negate a need for an ultrasound, which may or may not be true if you are only considering ovarian cancer, but I don’t think will reflect usual cirumstances of practice. The other 99.77% of women who have these symptoms but who don’t have ovarian cancer may have something else, serious or not, wrong. These women too need appropriate investigation.
The big issue is what will happen when GPs do as NICE ask. On page 50, theoretical workings out for what would happen under different guidelines occur. NICE are telling GPs that it happens like this  :
“Distribution of cases according to test results in a theoretical cohort of 100,000 women with symptoms consistent with ovarian cancer presenting to primary care. Assumed prevalence of undiagnosed ovarian cancer is 0.23% in women with such symptoms.
Ovarian cancer
Referral strategy                                                                                         Test result                          Yes                  No                        Proportion with ovarian cancer
Refer if CA125 is positive                                                                        CA125 positive                   179                 21,949                0.82%
Don’t refer if CA125 is negative                                                            CA125 negative                      51                  77,821              0.06%
Refer if ultrasound is positive                                                               ultrasound positive           196                 16,961                1.16%
Don’t refer if ultrasound is negative                                                  ultrasound negative             34                82,809                 0.04%
Refer if CA125 or ultrasound is positive                                   CA125 or ultrasound             223                 34,920                  0.64%
positive*
Don’t refer if CA125 and ultrasound are negative             CA125 and ultrasound                    7                 64,850                  0.01%
negative *
Refer if CA125 and  ultrasound are  positive                           CA125 and  ultrasound            152                3,991                    3.81%
positive *
Don’t refer if CA125 or ultrasound is
negative                                                                                                 CA125 or ultrasound              78                          95,779                   0.08%
negative*
* assuming conditional independence”
Currently, standard practice would be an ultrasound first in primary care. Doctors have long been told that Ca-125s are not useful screening tests because they are not terribly specific nor sensitive for ovarian cancer. NICE are asking us to change to CA-125 first in women with lower abdominal/pelvic symptoms. However, as the table shows, ultrasound has a higher positive predictive value, and a negative ultrasound is more reliably truly negative than a negative  Ca-125.
Something else will happens, however. 21,949 + 179 women have a positive Ca-125 (total, 22,128)out of every 100,000 women with symptoms suggestive of ovarian cancer. To  find the 179 women with ovarian cancer, all these 22,128 women will need further investigated. NICE recommend ultrasound as first line, but then say that ” If the ultrasound, serum CA125 and clinical status suggest ovarian cancer, perform a CT scan of the pelvis and abdomen to establish the extent of disease. Include the thorax if clinically indicated”. I doubt it that ultrasound will be conclusive in all these women and suspect that CT scanning, with attendant radiation doses, will be used to try and delineate the ovaries in many.
The Daily Telegraph reported that the guidelines, saying “Campaigners say hundreds of lives could be saved a year if GPs were quicker to spot symptoms of the disease – dubbed a “silent killer” because it is hard to diagnose early enough.”. In fact, the same NICE guideline says : “It is not known if earlier recognition and referral will translate into earlier stage at diagnosis.” and “Examination of all the evidence  found no association, one way or the other, between the duration of symptoms on the outcomes studied.”
Clearly, prompt diagnosis and treatment is good for many reasons. But there is a major gear shift being made by NICE which is being supported by theoretical rather than real life data, and which is lending itself to an enormous raft of false positive testing. I don’t think it’s clear that this change is a good one.  We have managed to get ourselves into great difficulty with PSA screening. The potential for a similar muddle with Ca-125 testing is just as big; there are large unanswered questions about using this test as a first line, and I am disappointed that NICE have not raised this as a research recommendation.

15 Responses to “NICE guidance on ovarian cancer diagnosis”

  1. Dr Grumble April 28, 2011 at 7:22 am #

    I am no expert in this area but was very surprised by this recommendation. We have been told again and again that CA-125 should not be used for screening. Doutbless there were good reasons. You have nicely highlighted the unanswered questions.

    Everybody wants it to be Christmas. We have a nasty disease that is difficult to diagnose. There is a blood test. There are lobby groups from the something-must-be-done brigade. So something is being done. But will women live any longer as a result?

    As you have pointed out, the clinical question is not whether or not the patient has ovarian cancer. The question is which of the many things that might cause the symptoms listed is the actual cause. You get the impression that they have come at this from the wrong end.

    It is reminiscent of all the guidelines our junior doctors are now expected to follow when patients are admitted. The managers really think that all they need to do is follow the instructions. For pneumonia this, for a urinary tract infection that and so on. But patients don’t come in with these diagnoses stamped on their heads. Sometimes we have elderly people who might have pneumonia or might have a urinary tract infection or might have something else altogether. You can’t deal with the problem of differential diagnosis by considering just one condition.

  2. Margaret McCartney
    margaretmccartney April 28, 2011 at 12:15 pm #

    absolutely….there were three patient/carers on the guidelines group, and one GP and no public health doctors.

    Most of these women with symptoms won’t have ovarian cancer – so what else do they have ? – who represented that large group on the guidelines committee? –

  3. Peter M B English May 3, 2011 at 10:53 am #

    I have previously been very impressed by much of NICE’s work.

    This one has bothered me since I first read about it. It’s getting very close to treading on the national screening agency’s toes, by recommending a “diagnostic” test for a very common symptom set.

    But this blog has identified and clearly described a more important failing. Guidance is much more straight-forward when the starting point is at or after the point at which a condition is diagnosed. This guidance starts with a symptom set which identifies roughly 400 women who don’t have the condition for every one who does. (“NICE say that only 0.23% of women with these symptoms will have ovarian cancer.”) So it is giving guidance about the diagnosis of one specific condition that most women with the symptom set won’t have; rather than considering the appropriate management of all of the women in the group; and by coming at it from a blinkered point of view (with representatives from ovarian cancer interest groups) it has failed to view this holistically.

  4. Anna Sayburn May 3, 2011 at 11:56 am #

    A very good analysis of a troubling question, Margaret. Hamilton et al published a good analysis of ovarian cancer symptoms recently in the BMJ (http://www.bmj.com/content/339/bmj.b2998.long) which showed only abdominal distension had a positive predictive value higher than 1%, and also that speedier diagnosis after initial presentation of symptoms was unlikely to save more than about 3 months in terms of time to treatment.

  5. Margaret McCartney
    margaretmccartney May 4, 2011 at 9:30 pm #

    Somewhat predictably – here’s a press release, at the bottom, from the Eve charity, saying that women are calling in thinking there is a new screening test for ovarian cancer.
    I don’t think Eve’s press release makes the situation clear. It does not state that there is diagnostic issue with women presenting with these symptoms. This is not just about the attempted exclusion of one rare cause of these symptoms (ovarian cancer). Again, I’m disappointed.

    NICE actually says this:
    “Carry out tests in primary care (see section 2.2 on page 21) if a woman (especially if 50
    or over) reports having any of the following symptoms on a persistent or frequent basis
    – particularly more than 12 times per month
    persistent abdominal distension (women often refer to this as ‘bloating’)
    • feeling full (early satiety) and/or loss of appetite
    • pelvic or abdominal pain
    • increased urinary urgency and/or frequency.” – which is slightly different from what Eve say.

    Release date: 4 May 2011
    Ovarian cancer test news is misunderstood
    says gynaecological cancer charity The Eve Appeal

    In light of recent media coverage following the introduction of new NICE guidelines on ovarian cancer, The Eve Appeal and UCL Gynaecology Cancer Research Centre are concerned that women are misunderstanding the advice reported on CA125 blood tests.
    Says Robert Marsh, CEO at The Eve Appeal “ The CA125 is an existing blood test currently available on the NHS to patients who have, or are suspected of having, ovarian cancer. Our concern is that women’s perception of the NICE guidelines as reported in the media is that this is a new test available for £20 to women who want to check that they don’t have the disease. This is not the case.”
    Under new NICE guidelines, one of the recommendations is that GPs and practice nurses should offer the CA125 blood test earlier, and in primary care, to women who have experienced one or more of the following symptoms for some time or if they occur frequently (ie more than 12 times a month), especially in patients over 50 years of age.
    • persistent abdominal bloating
    • difficulty eating or feeling full quickly
    • pain in the abdomen or pelvic area
    • needing to pass water urgently or more often than usual
    High levels of CA125 protein in the blood may indicate the presence of ovarian cancer however the readings can be raised in women with other conditions and even some healthy women have naturally high levels. An elevated level of CA125 does not necessarily mean ovarian cancer.
    Professor Ian Jacobs, UCL Gynaecological Cancer Research Centre and Medical Director of The Eve Appeal comments “Only 1 in 500 women who have the symptoms above will actually have ovarian cancer.” Professor Jacobs also highlights “NICE estimates that only 1 in 157 women with abnormal CA125 and 1 in 26 women with an abnormal CA125 and ultrasound will have ovarian cancer. So for each woman diagnosed with ovarian cancer, a large number of women will have abnormal tests and some proceed to surgery with the risks that involves.
    The CA125 blood test is therefore being investigated as part of Professor Jacobs’ ovarian cancer screening trials – UKCTOCS – to investigate whether or not the test, in combination with ultrasound, can pick up ovarian cancer early ie before the occurrence of symptoms.
    The new NICE guidelines recommend that women with high levels of CA125 should then be offered an ultrasound scan of their abdomen and pelvis. If this scan suggests ovarian cancer they should be referred to a gynaecologist within two weeks.
    “Although 4,600 women die from this disease in the UK each year, GPs may only see one case in five years so this is a major step towards moving ovarian cancer up the primary care agenda. By encouraging GPs act on these symptoms early, we hope this practice will lead to diagnoses of the disease at an earlier stage and help save lives.” Continues Robert Marsh of The Eve Appeal.
    “As a gynaecological cancer research charity we have received calls from women wanting to know more about ‘this new ovarian cancer test’. This is a worrying misunderstanding and one that we are keen to clarify.” says Robert Marsh.
    “Our advice to women is to be aware of the signs and symptoms and to visit your GP if you have any concerns – for more information go to http://www.eveappeal.org.uk”
    – ends –

    Further information:

  6. danielle giesbrecht May 26, 2011 at 9:25 am #

    i have been getting progressively sicker as the months drag on. i have had urologists deny me access-bcuz its NORMAL to urinate blood. i have had labs report NO blood in urine when you CAN actually SEE the blood….got reported back as-n/a.. guess what? i got pictures!!!!! their asumption?? my monthlys…whicvh i HAVE NOT had in over 2 years. the report of “NOTHING” from a urologist-on finding caculi on kidney…he NEVER told me..I found out a year later when i bhad another CT scan and it was compared to that one!! a hospital that spilled my urine{my daughter witnessd this!} and told me..its ALL good..ON THE FLOOR??? seriously?? how about a NEPHROLOGIST NOT KNOWING WHAT RENAL COLIC IS??? She said it was all in my head!!! We dont live in a third world country..do we? well the time has come to tell the MEDIA my story. there is sooo much more but now i am fighting for help due to “ovarian cancer” being at the top of the symptom list.. BUT OH WAIT>> 47 IS TOO YOUNG??? OK SO SORRY I DID NOT REALIZE CANCER WAS BECOMING SO PICKY!! THIS WHOLE MESS IS CRAZY!! I DONT Have i life… i MERELY EXSIST.. WANNA JOIN ME?? or DONT YOU ALL FANCY BEING A BEDRIDDEN PERSON WHO IS HAVING A GOOD IF SHE MADE IT TO THE BATHROOM THIS TIME??? YEAH ALL THIS ISNT GOING TO MATTER TO”important”PEOPLE,RIGHT? LIFT THE CARPET FOLKS AND SWEEP IT UNDER.. WELL ALL I CAN SAY NOW?? I AM IN FOR A HORRIBLY,PAINFUL DEATH..AS MUCH AS I WOULD LOVE FOR IT TO TAKE ME QUICKLY? THANX TO OUR THIRD WORLD SERVICE? I WILL BE SURE TO GIVE OUR SUMMER MAGGOTS AND FLIES A GOOD FEAST.. ITS JUST AS GOOD AS I AM GETTING NOW!!! GOD BLESS

  7. Helen Johnson June 21, 2011 at 7:02 pm #

    Ovarian cancer, like cervical cancer, rarely gives rise to symptoms until it is too late for effective treatment so why do we not look for the early signs as we are doing for cervical abnormalities? It was my practice, when taking cervical smears, to follow up with a palpation of the abdomen and a bi-manual examination of the pelvis. Provided that one has made sure the bladder is empty, ovarian tumours are readily palpable. In this way I found more ovarian tumours ( solid or cystic or both ) than positive smears. How many of these were malignant, I do not know but they were all potentially malignant and a hazard in pregnancy. Patients occasionally had mild discomfort such as urinary disturbance or dysparunia and were relieved to know that a cause had been found. It is ironical to reassure a woman’s fear of cancer when telling he that her cervix is normal if she has a potentially malignant ovary lurking in her pelvis.

  8. Margaret McCartney
    margaretmccartney June 22, 2011 at 9:29 pm #

    dear Helen
    we could say that all our ovaries are potentially malignant. When we are screening we are looking for disease outwith the symptomatic pathology that most research is based on. Studies have been done looking at screening women at high risk for ovarian cancer with ultrasound and ca-125 and that has been unsuccessful in reducing death rates from ovarian ca. I genuinely don’t think that ovarian cancers at an early stage are readily palpable, and the NICE guidelines do cite evidence of this, best , mgt

  9. Dr H L KAPOOR July 31, 2011 at 2:23 am #

    there are reasons to feel alarmed at the raised values of tumour markers especially PSA and CA 125 in asymptomatic or patients with mild symptoms.These tests are highly rated as indicators of malignancy but the bottom line is that these need to be supplemented with other definitive diagnostic procedures to validate their significance.Take these tests with a little “pinch of salt”and not “gospel truth” lab variations and many factors will alter or raise these values.Yes these tests have definite follow up values after treatment. Keep your clinician informed and remain in touch and relax in the meantime

  10. L Anderson April 16, 2012 at 11:13 pm #

    My wife was diagnosed a year ago with late stage 4 Ovarian Cancer, she died 5 months later. She seemed until then quite healthy and even in hindsight could not have been diagnosed earlier. Comments from professionals label this disease as a silent killer, by the time it is found it is too late!
    A proper screening program is the only hope, too late for my wife. Posters, education and information all give symptoms which are too late!

  11. Chris June 21, 2012 at 10:07 am #

    Can I offer a patient’s perspective, if anyone is still reading this? I was recently given a CA125 test (without being specifically asked) as a battery of blood tests when I went to my GP complaining about repeated virus infections (not over months, but years- that’s how long it takes for things to get noticed in my neck of the woods). The first I knew about CA125 was when I went back to see what the results of the tests were, was told about CA125 and its role as an indicator of ovarian cancer, that mine was elevated (around 60) and that my GP was making an urgent appointment for an ultrasound. Ultrasound inconclusive- just suspicious enough that the consultant radiologist recommended an MRI. Nothing on the MRI. By this stage, I was of course chewing chairlegs and had more papers on CA125 downloaded on my laptop than I really want to have to know about. Next, repeat CA125. Still about the same, so another ‘urgent’ appointment to see a gynaecologist.

    I haven’t been able to track down NICE’s guidelines on using CA125 for screening on asymptomatic women, presumably because there aren’t any- that is, no one thinks it such a great idea. So far this has cost the NHS two ultrasounds (in one session), one MRI, three GP appointments and (except that I am now bailing out into the private sector) one gynaecologists’s consultation. It has cost me enormous anxiety over a period of three months, and time out of concentrating on running my business. I realise that my righteous indignation may yet come back to bite me if I am eventually diagnosed with something nasty- but if that is the outcome, will it be significantly sooner than if I had not been seen until I complained about symptoms? Looking at the statistics, it seems to me that using this test for screening asymptomatic women would cost an enormous amount of money and anguish to little good effect (and please, don’t underestimate the extent of that anxiety). I have the impression that once the train labelled ‘possible cancer’ leaves the station, it takes a brave doctor to tell a patient she can get off. Using CA125 as a routine screen would result in that train being very crowded.

    I do realise that the original blog is discussing advice to use CA125 on women presenting with symptoms, but if my GP had the bright idea of including CA125 in a so-called ‘well woman’ battery, I don’t suppose he is alone. So, I just thought I’d give my experience, and my reactions to them, an airing. Thanks for listening (if anyone is).

  12. Margaret McCartney
    margaretmccartney June 21, 2012 at 11:34 am #

    dear Chris
    I am so sorry to hear this. The Ca 125 test is not evidenced except in investigations to look at lower abdominal/pelvic symptoms, and even then it is not great (I only really use it when ovarian ca is suspected, and even then ultrasound I think is a better test. I’ve written about the NICE guidelines in my book as I don’t think they are helpful.) I don’t think you are alone either. Unfortunately, many women will view this scenario as ‘thank goodness I’ve not got cancer’ rather than ‘I’ve been subjected to numerous tests that weren’t really indicated in the first place and caused me substantive anxiety”. We don’t hear stories like yours enough, and I’m glad you’ve written it down. I think until we hear proper anger from patients about the harms of overtesting and overinvestigation we will keep going round in harmful circles. I will tweet this out. thank you.

  13. Chris June 21, 2012 at 5:04 pm #

    Very many thanks for responding. I am still torn between hopping mad and unresolved terror (I’m a real wimp)- it’s very difficult to jump off the find-the-cancer train when there are people with suitable qualifications telling you you should stay on. I’m trying to hang on to hopping mad. Ah well, seeing gynae next week- I hope he understands that there’s only one answer I want :-) Anyone advancing on me with a scalpel and consent form (‘it would be a really good idea to have a look and make sure…’) will have to be pretty persuasive. Thanks again, Chris

  14. mel August 9, 2012 at 9:31 am #

    Chris,
    Im in a very similar position and I sympathise.
    How did the appt with the private gynae go?
    I can give u my email If you would rather keep it private.
    Mel
    Lancashire

  15. Christine November 1, 2014 at 10:03 am #

    My GP advised me of my elevated ca125 on Monday. I had the USS yesterday. They said it was inconclusive, although there are no “large masses”. I should go back to my GP in 2 weeks so he can think about “other causes” once he has the USS results. There are “other causes” that are as scary as ovarian cancer.
    I had breast cancer 12 years ago, when diagnosis was swift and thorough treatment followed rapidly, so I am still here.
    Gnawing chair legs doesn’t begin to describe how I feel now. Will someone please, please explain why it takes 2 weeks to get the USS results to the GP?

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