The first thing to say is that tubal cancer is really a slightly provocative title because what it’s designed to do is to make the audience think about the fact that what we used to think of as high grade serous ovarian cancer, which is the commonest and one of the most lethal types of ovarian cancer, actually starts at the end of the fallopian tube in the majority of cases. Because it’s such a nasty cancer and there isn’t currently a screening programme for it to try and detect it early there’s been decades of research gone into trying to find a solution to this massive problem. Because at the moment around a quarter of all such cancers in the United Kingdom will present as emergency cases for the first time to A&E with ascites, fluid in the abdomen, bowel obstruction, it’s a really nasty cancer. Unfortunately the survival rates aren’t great and the UK appears to lag behind many other countries with this and there is no country that currently has a screening programme because so far no screening test has been shown to definitively save lives with this cancer.
The UK has actually been a world leader in this and the UKCTOCS trial, which published in The Lancet a couple of years ago showed a suggestion of a mortality benefit but this wasn’t confirmed on the primary statistical analysis which was pre-specified. It has been statistically significant on secondary analyses but, not surprisingly, The Lancet was unwilling to make that the headline story. So, as a result of that, the trial has had to go on for longer in terms of the follow-up period and we’re hoping to get the results of that in the public domain; I believe the authors are releasing that in 2019. At that point we’ll have a definitive answer as to whether screening, in this case using an algorithm that looks at the rate of change of the tumour marker CA125, whether that actually saves lives or not. If it does save lives then we’re hopeful in the UK that the national screening committee will look favourably at it and think about introducing it as a national screening programme for all women over the age of fifty.
The other area I was talking about was in high risk women, in other words women with a known genetic predisposition such as BRCA1 and BRCA2 carriers, they’re also Lynch Syndrome carriers and carriers of more recently discovered but less common genes which also can increase the risk of ovarian cancer. The UK has also been a bit of a world leader in this because we were also involved with a study called the UK Familial Ovarian Cancer Screening Study, or UKFOCSS. This recruited over 4,000 women who had a family history or a known genetic mutation that predisposed them to ovarian cancer. We screened them using the same algorithm but more frequently, they were screened three times a year rather than once a year as happened on the UKCTOCS trial. Because it was a high risk population we were not able to randomise them to a non-screening arm because we didn’t feel the women themselves would accept that because they know they’re at very high risk, why would they agree to not being looked at regularly? And then also the clinicians, we felt… in fact there was a meeting and clinicians voiced their opinions and they agreed that it really wasn’t going to be feasible to run such a trial. So it was a prospective interventional trial where the women were screened, as I’ve already discussed, and then if their results were concerning they would eventually end up with an appointment with a gynaecological oncologist to decide whether or not they should have surgery or not. These were women who really should be having risk reducing surgery because they’re deemed to be high risk. So they would normally be offered a standard medical care removal of their fallopian tubes and ovaries, usually as a laparoscopic procedure, a keyhole procedure. These women, the main reasons for not wanting to go ahead with that surgery is usually that they’re too young, they haven’t yet completed their family, so they don’t want to become infertile, and they don’t want to have to take hormone replacement therapy for a long time as well. Because if they had their surgery at, say, the age of forty they’d be looking at taking HRT for a decade or more. So you can understand why these women don’t necessarily want to jump straight in and have the risk-reducing surgery.
So the long and the short of it is we did manage to downstage the tumours by using this method and we downstaged them so that the majority of them were at stage 3a or below. That means only microscopic disease outside of the pelvis. As a result of that, nearly all of them were completely cytoreduced, meaning at the end of their first operation they had had all of the tumour removed visibly. Of course they then go on to have chemotherapy.
It’s not possible to comment on a survival advantage or a mortality benefit in this situation because it’s not a randomised trial but our expectation would be that this downstaging, which resulted in a much higher rate of complete cytoreduction, and I might add with less invasive surgery because they were much more likely to get away with just a hysterectomy and omentectomy only and not need other things, and also a lower chance of needing neoadjuvant chemotherapy. All of these factors together would suggest that these women are now in a very good prognosis group. So we can’t say that we’ve cured them, if I’m being honest we’re not expecting to have cured them, because most of them did have metastatic disease at the point at which they were detected, but they would now be expected to survive much longer. We don’t, as yet, have evidence of that but it’s a very good step in the right direction. In fact, it’s been such a good step that I’m delighted to be able to say that we’ve recently received ethics committee approval to run a pilot NHS screening programme for BRCA carriers and we’re hoping to launch that later this summer.
Is there a potential to double up with this screening for other cancer types?
If one had an ultrasound based programme, which we’re not and I could talk to you about why ultrasound is not the right way to do it, you would of course be looking at the uterus at the same time. For Lynch Syndrome carriers they’re at increased risk of endometrial cancer more than they’re at an increased risk of ovarian cancer. Actually the data on ultrasound for that situation isn’t so great.
Looking to the future, and in fact one of our groups at UCL is looking at this very closely, there is the concept of trying to detect ovarian and other cancers on smear samples because obviously women are used to having them anyway, they currently get them every three years between the ages of 25 and 50 and then five-yearly thereafter until they’re 64. That’s the ideal opportunity – if there was a test that could detect high grade serous cancer, that most people think of as ovarian cancer even though it starts in the fallopian tube in the vast majority of cases, if there was a test that could pick that up but the sample you collect in order to do that is just the smear, that would be absolutely wonderful. There’s also the possibility of self-collected samples, for example a woman may use a tampon specifically designed for this process and it may be possible to use the genetic material in that tampon, looking at issues such as epigenetics, which is the genetic modification that occurs to the DNA as a result of exposure to environmental factors, for example. There is some very promising work coming out of UCL and other institutions suggesting that epigenetics can be a very accurate marker for the presence or absence of cancer or the presence of cancer risk. This is going to be the future.
What the UKCTOCS and UKFOCSS studies have shown is that you can downstage tumours, in other words you’re picking them up before they cause symptoms and then you’re detecting them when they’re at an earlier stage. That puts them into a better prognosis group but the difficulty with high grade serous ovarian cancer, or tubal cancer, let’s just call it high grade serous cancer, is that you have to detect it really, really early to be certain of a cure. At the moment we haven’t got evidence that lives have been saved with this screening so we have to wait for the results of the UKCTOCS trial before instituting it as a national screening programme for the general population. As far as the high risk population are concerned, they really should be having their risk reducing surgery but until they’re ready to have it in 2018 the safest thing they can do is be surveyed using this risk of ovarian cancer algorithm, or ROCA as it’s called, which looks for changing levels of CA125. Because they are less likely to be diagnosed with a very advanced stage ovarian cancer if they’re being surveyed using this technique.
