Ovarian cancer screening trial did not save lives

“The effort from the start was to save lives of women with ovarian cancer. To build evidence for a screening programme that the NHS could introduce. To have an impact on the lives of thousands of women who are affected by ovarian cancer each year.”

Professor Usha Menon, a gynaecologist at University College London, has been working to improve ovarian cancer diagnosis since the mid-90s. Specifically, she’s worked to pick up ovarian cancers earlier, when treatment is more likely to be successful.

The benefits of earlier diagnosis are clear – around 90 in 100 women diagnosed with early-stage ovarian cancer survive for 5 years or more, compared with just 3 in 100 women with late-stage disease.

But spotting ovarian cancer early enough to make a difference is difficult. Symptoms can be vague and are usually shared with other, more common, and often less serious, conditions.

To try and make the shift needed, Menon and others looked to screening.

In 1999, Menon joined Professor Ian Jacobs’ team and together they set up the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS).

20 years later, the results are in.

Putting ovarian screening to the test

In the 80s and 90s, researchers were hunting for tests that could pick up ovarian cancer earlier.

Two strategies seemed to hold promise – one based on ultrasound and the other looking at changes in the levels of a protein called CA125 in the blood. Jacobs and Menon selected these to put to the test in a large, randomised control trial.

Alongside other organisations, our forerunners funded UKCTOCS. The goal – to prove if either approach could save lives from ovarian cancer.

The trial involved 202,000 women aged 50 to 74 across the country:

• Half the women formed the ‘control’ group and weren’t given any screening.
• A second group were given a yearly ultrasound scan to look for abnormalities in the ovaries that could be a sign of cancer.
• A third group were given an annual blood test to measure their CA125 levels.

CA125 levels are often raised in women with ovarian cancer. But as levels can vary between women, the team developed a more sophisticated approach, measuring how each woman’s CA125 levels change over time. They called the approach the ‘Risk of Ovarian Cancer Algorithm’ (or ROCA, for short).

After each blood test, ROCA generated a risk-related score that would affect what happened next:

• Women with ‘normal’ ROCA scores continued with annual screening.
• Those at ‘intermediate risk’ had another blood test 3 months later.
• Those at ‘elevated risk’ had another blood test and an ultrasound within 6 weeks.

The trial recruited women from 2001 to 2005, with yearly screening continuing until 2011. Then it was a waiting game.

It takes a long time to determine whether screening affects deaths from the disease, so the researchers had to follow the participants up until 2020 to be sure if there was the impact or not.

What did UKCTOCS find?

The ultrasound screening strategy wasn’t able to detect ovarian cancers earlier or save lives.

However, data from the blood test group was more interesting.

“What we found is with the strategy that used the blood test, we did pick up women with ovarian cancer earlier than in the control group where women had no screening. But in both screening groups we were not able to save lives.”

In the blood test group, the incidence of early stage (1 or 2) ovarian cancer was 39% higher than in the no screening group which is a promising indicator. But this isn’t enough to show the benefit of screening – the balance of a range of benefits and harms must be taken into account.

The most important target for a screening strategy is reducing deaths from the disease. And unfortunately, this goal was not met.

For Menon and the team, the results were deeply disappointing. Menon thinks there are a few reasons that despite promising signs, the CA125 blood test strategy didn’t ultimately save lives. “We didn’t pick up enough women early and we didn’t pick up cancers early enough.”

The team also noticed that women who were picked up earlier didn’t seem to respond to the standard treatment as expected. They’re looking at this data in more detail now.

“What we need to do now is to analyse very carefully what treatment people on the trial received. And there are a lot of insights that I think the trial can provide.”

An enduring legacy

All women who took part donated their data and blood samples for researchers to use in secondary studies. And in the group 50,000 women who had yearly blood tests, this has created an extremely rich resource. “What we have is a very unique set of annual samples spanning 7 to 11 plus years,” says Menon.

The team look forward to “using and sharing the data and the samples with researchers the world over. So that we don’t leave any stone unturned and we learn everything we can.”

For the women who were diagnosed with ovarian cancer during the study, these blood tests offer a snapshot into what was happening in the years leading up to diagnosis.

Menon says these samples are already being used to evaluate promising new tests coming through. “We have the ability to use this bank and the earlier samples to see if new tests could have performed better than CA125 and ROCA.” This data will be invaluable in guiding future trials.

The data also provide a unique opportunity to study how ovarian cancer develops, something Menon is keen to explore further. “We’re hoping that people who do natural history modelling will use this data to try and understand more about ovarian cancer.”

This knowledge could lay the groundwork for new approaches. Because as Menon points out “all our attempts for early detection are based on understanding the disease better”.

And it doesn’t stop with ovarian cancer.

Beyond ovarian cancer

“There were also women who took part who were diagnosed with other cancers – breast cancer, bowel cancer – as well as other diseases. And because they were willing to share their data and samples with researchers, we also have lots of groups who are working on early detection of other cancers using the UKCTOCS samples.”

These samples are a crucial part of the legacy of UKCTOCS, which will help guide future studies. “It’s a very rich resource for which we are hugely grateful to the women for sharing with the wider world.”

Menon says another legacy of the trial is to reaffirm how important it is to look at lives saved in big screening programmes.

“If we had just focused on early detection and what percentage of women are diagnosed at stage 1 or 2, we might have got the wrong answer. That’s why we followed everybody for so long – we needed to find out if diagnosing women earlier will translate into lives saved, but it didn’t.”

The road ahead

While the trial involved many from what Menon calls the ovarian cancer community, it’s not been the only focus for the community.

“There’s a lot of efforts focused on symptomatic women – trying to decrease diagnosis at advanced stage and the number of women diagnosed through A&E.”

There have also been many improvements in ovarian cancer treatment in the last decade.

Researchers are also looking into better risk management strategies for high-risk women.

“In UKCTOCS, we tested screening in the general population. But there’s a small group who are at an increased risk of ovarian cancer because they have a genetic mutation.” For these women, studies are exploring how to refine risk reducing surgery, as well as more frequent screening.

It’s been a long road for Menon and the UKCTOCS team and they’re not done yet. Looking back on the last two decades, Menon says the team are indebted to the women who took part and to everyone who supported the trial.

“I think we can be proud of the effort – it was a huge trial spanning 20 years. Everyone came together and supported it. It’s a testament to the research that can be done in the NHS.”

Katie

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