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.
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%
Don’t refer if CA125 and ultrasound are negative CA125 and ultrasound 7 64,850 0.01%
Refer if CA125 and ultrasound are positive CA125 and ultrasound 152 3,991 3.81%
Don’t refer if CA125 or ultrasound is
negative CA125 or ultrasound 78 95,779 0.08%
* 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.