Ovarian Cancer Screening May Save Lives

Fran Lowry

December 17, 2015

The largest trial of ovarian cancer screening — which compared annual screening with no annual screening in more than 200,000 women, who were followed for 14 years — has concluded that screening could reduce mortality from the disease by about 20%.

However, researchers from the United Kingdom Collaborative Trial of Ovarian Cancer (UKCTOCS) caution that longer follow-up is needed to determine the ultimate mortality reduction from screening and to determine whether screening in the general population is cost-effective.

"First-Ever Evidence"

Dr Ian Jacobs

"This is the first-ever evidence to suggest that screening for early detection of ovarian cancer may save lives," Ian Jacobs, MD, president and vice-chancellor of the University of New South Wales in Sydney, Australia, told Medscape Medical News.

Dr Usha Menon

"More follow-up is needed, but the results are encouraging and exciting and open up the possibility that many lives could be saved," said Dr Jacobs, who led the trial with Usha Menon, MD, from the Institute for Women's Health, University College London, United Kingdom.

"We have the first evidence that ovarian cancer screening can save lives, but we need further follow-up to confirm the findings," added Dr Menon.

"However, screening is not without harms, which include some women undergoing surgery to find they only have benign ovarian lesions or normal ovaries," she told Medscape Medical News.

 
Our findings offer hope to the women and also to the research community that we can intervene to bring about change in the disease course.
 

"Our findings offer hope to the women and also to the research community that we can intervene to bring about change in the disease course. This, in turn, will provide fresh impetus for further research work in this area. In the medium term, we hope that we will be able to confirm, through follow-up of the trial participants for 2 to 3 years, the mortality reduction and determine the magnitude of the impact. This, along with our cost-effectiveness analysis and risks–benefits ratio, should allow a comprehensive assessment of whether ovarian cancer screening should be offered to women aged 50 and over in the general population," Dr Menon said.

The long-term outcomes from this large screening trial were published online December 17 in the Lancet.

The researchers randomized more than 200,000 women from June 2001 to October 2005 to one of three group: 50,624 underwent annual multimodality screening, which consisted of a serum cancer antigen 125 (CA125) test interpreted with the risk of ovarian cancer algorithm (ROCA) plus ultrasound; 50,623 underwent annual transvaginal ultrasound screening alone; and 101,299 underwent no screening.

When screening ended in December 2011, the researchers had 345,570 multimodality screens and 327,775 ultrasound screens to evaluate.

The women from 13 centers in the United Kingdom were followed for 14 years.

All women were postmenopausal, 50 to 74 years of age, and had no history of bilateral oophorectomy, ovarian malignancy, increased risk for familial ovarian cancer, or nonovarian malignancy.

At a median follow-up of 11.1 years (interquartile range, 10.0 - 12.0), ovarian cancer had been diagnosed in 1282 (0.6%) women — 338 (0.7%) in the multimodality group, 314 (0.6%) in the ultrasound group, and 630 (0.6%) in the no-screening group.

Of the women who died of ovarian cancer, 148 (0.29%) were in the multimodality group, 154 (0.30%) were in the ultrasound group, and 347 (0.34%) were in the no-screening group.

Earlier Detection, Reduced Mortality with Screening

When the researchers analyzed the 14-year data, they found a reduction in the rate of death from ovarian cancer of 15% (95% confidence interval [CI], –3 to 30; P = .10) in the multimodality group and of 11% (95% CI, –7 to 27; P = .21) in the ultrasound group.

In the multimodality group, the reduction in mortality was 8% in the first 7 years and 23% in the subsequent 7 years.

In the ultrasound group, the reduction in mortality was 2% in the first 7 years and 21% in the subsequent 7 years.

When women who had undiagnosed ovarian cancer when they joined the trial were excluded from the analysis, the reduction in mortality rates related to screening improved.

Overall, there was an average reduction in mortality of 20% in favor of multimodality screening. The reduction in mortality was 8% in the first 7 years and 28% in the subsequent 7 years.

Cancer was detected at an early stage in more patients in the multimodality group than in the no-screening group (39% vs 26%; P < .0001).

"The primary analysis did not reach conventional statistical significance, so we cannot state definitively that screening saves lives, but it seems likely. Further follow-up is needed to be sure," said Dr Jacobs.

"The screening test involves a simple blood test, which can be done anywhere and sent to a lab," he said. This could have an effect on the more than 100,000 deaths from ovarian cancer each year around the world.

 
I see this first evidence that screening can save lives from ovarian cancer as a paradigm shift in our approach to the disease.
 

"I see this first evidence that screening can save lives from ovarian cancer as a paradigm shift in our approach to the disease," he said.

"Research now needs to accelerate to refine screening and confirm the benefit, so that, in due course, widespread national screening programs can be put in place," Dr Jacobs said.

Despite the encouraging results from UKCTOCS, detection of cancer was limited in both screened groups — at 59% in the multimodality group and 51% in the ultrasound group — write René H.M. Verheijen, MD, and Ronald P. Zweemer, MD, from the UMC Utrecht Cancer Center in the Netherlands, in an accompanying comment.

"If only 59% of ovarian cancer cases are detected by screening plus ultrasound, we will need to focus on why and how screening — as undertaken within UKCTOCS — still has a significant, but delayed, survival effect. Trying to unravel the mechanism behind this effect so that it can be improved should have a high priority," they write.

CA125 With the New Algorithm Boosts Detection

Ovarian cancer detection rates are better when the CA125 test is interpreted using the new algorithm, Dr Jacobs and his colleagues note.

ROCA is based on changes in serum CA125 levels over time, rather than on traditional fixed CA125 cutoff values, as previously reported by Medscape Medical News.

In an earlier study, the algorithm detected 87.1% of invasive epithelial ovarian or tubal cancers, compared with 41.3% with a fixed CA125 cutoff above 35 U/mL, 48.4% with a cutoff above 30 U/mL, and 66.5% with a cutoff above 22 U/mL (J Clin Oncol. 2015;33:2062-2071).

"On the basis of current evidence, the multimodal strategy using CA125 in the risk of ovarian cancer algorithm, followed by ultrasound as a secondary test where needed, seems to have the highest sensitivity or detection rate, the lowest false-positive rate, and the best evidence for a mortality reduction," Dr Jacobs reported.

"Some women will wish to access screening on an individual basis, having taken the view that, for them, the balance of benefit, harm, and cost makes it worthwhile. This decision will depend upon many factors, including a woman's level of risk of ovarian cancer, her views on health and screening, and the cost involved. Our advice is that women considering accessing screening should make a fully informed decision, having taken medical advice," he explained.

Longer Follow-up Needed

Experts agree that longer follow-up is needed to determine how effective annual screening will turn out to be.

"Although still at an early stage, the initial results from the UKCTOCS trial into screening for ovarian cancer are promising," Clare Mckenzie, MD, consultant gynecological oncologist and vice president of the Royal College of Obstetricians and Gynaecologists, said in a statement.

So far, results suggest that approximately 15 deaths could be prevented with CA125 screening for every 10,000 women screened, Dr Mckenzie noted. "However, for every woman with a positive screen who underwent surgery and was found to have ovarian cancer, two did not," she added.

"The early detection of ovarian cancer, and hence early treatment, has the potential to save lives. However, longer follow-up is needed to determine how effective the test is. Women who are worried about ovarian cancer should talk to their doctors, who can explain their risk of cancer and available tests," Dr Mckenzie said.

Benefits of Screening Modest

Dr Gary Leiserowitz

"This is the largest randomized controlled trial of ovarian cancer screening using two different screening approaches. The patients were followed for a prolonged period of time with very few patients lost to follow-up," said Gary S. Leiserowitz, MD, professor and chair of the Department of Obstetrics and Gynecology, and chief of the division of gynecologic oncology at the University of California Davis Health System in Irvine.

"Two other studies — one from Japan and the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial from the United States — were smaller, and neither showed statistically significant benefits to large-scale ovarian cancer screening. The UK trial showed some evidence of early detection with both multimodality and ultrasound, plus moderate reduction of mortality using post hoc statistical analyses. The effects were greater with longer follow-up," he told Medscape Medical News.

"The benefits were modest in this trial. Only 59% of ovarian cancers were detected early with multimodality, and 51% in the ultrasound group. A large number of women must be screened to see benefit. The authors estimate that 641 women must be screened annually to prevent one ovarian cancer death. It remains unclear whether these results are generalizable to a large population, and the cost-effectiveness of the strategy has not been calculated. The mortality reductions require a long time frame before significant differences are seen between screened and unscreened populations," Dr Leiserowitz explained.

"This UK study is the first to show a reduction in ovarian cancer mortality with ovarian cancer screening, which is at least hopeful, with the greatest effects seen with a combination of annual screening with CA125 followed by pelvic ultrasound if the CA125 is elevated," he said. "This study warrants further investigation, but also emphasizes that screening for low-prevalence cancers with tests that have limited sensitivity and specificity, such as CA125 and pelvic ultrasound, make it very difficult to show efficacy over no screening, and the cost-effectiveness has yet to be proven," he said.

Optimistic That Screening Will Save Lives

Dr Karen Lu

Karen H. Lu, MD, chair of gynecologic oncology and reproductive medicine at the University of Texas M.D. Anderson Cancer Center in Houston, told Medscape Medical News that she is very optimistic that ovarian cancer screening will eventually be proven to save lives.

"I think this is an incredible study and an incredible effort in more than 200,000 women for almost 15 years," Dr Lu said.

"While they did not find a significant difference in their primary outcome, they did find that there were more earlier-stage cancers identified in women who were screened, and they did find that in women who were screened for a longer period of time, there was a significant decrease in dying from ovarian cancer. That has never happened before. I believe that while the results from UKCTOCS are not practice-changing right now, they have a very real potential of being practice-changing in the near future," she said.

Reactions From UK Experts

Several experts from the United Kingdom provided their reactions to the findings in statements published on the UK Science Media Centre.

Ovarian cancer surgeon Christina Fotopoulou, MD, PhD, consultant gynecological oncologist at Queen Charlotte's Hospital, London, speaking on behalf of the Ovarian Cancer Action Research Centre, ia enthusiastic about the findings.

"The latest UKCTOCS findings are promising and a welcome step towards a screening method for ovarian cancer.... We've always been one step behind the disease, but a screening method would allow us to catch it at a stage that makes treatment more effective. While we're not there yet, and will need to wait for further study and definitive results, UKCTOCS shows that research in the field is gaining pace," she said.

However, two other experts questioned the statistics used in the study. Kevin McConway, PhD, professor of applied statistics at The Open University, said: "The problem with easily making sense of this study is that there are several different statistical analyses, and they all gave slightly different confidence intervals (a way of indicating how big or small the true reduction in mortality from screening might plausibly be). The primary planned analysis on their primary outcome (the Cox model on ovarian cancer mortality; at the top of table 3) showed reductions in deaths where the central estimate was reasonably substantial, but the confidence intervals included zero, so that was not a statistically significant result and, in the usual statistical terms, could plausibly be due to random variation only. But because of various features of how the data looked, the authors did other analyses (the Royston-Parmar model), which gave results that are broadly similar (reduction in deaths on the new screening method, multimodality screening, compared with no screening of 15% or 16%, with confidence intervals going from a little bit below 0% to somewhere round 30%). In addition, though, they did some other statistical analyses — splitting up the follow-up times in the Royston-Parmar model to 0 to 7 years and 7 to 14 years instead of looking at all the years together, using a different statistical test (the weighted logrank, or WLR, test), and omitting the women who had undiagnosed ovarian cancer when they first joined the study. Some of those did give larger reductions in deaths, two of which were statistically significant (just)."

"Now, doing these extra analyses can be seen as an appropriate post hoc response to how the data turned out to look (which in some respects weren't as they originally expected), and the authors give justifications for what they did. But equally, it is also the case that the more analyses done, the more likely it is that one of the results will come out as positive. I think the author's overall conclusion — that these results show promise but they need a few more years' follow-up to know exactly what's going on — may well be reasonable," he said.

However, the last sentence in the publication is very important, he pointed out. The researchers write: "Further follow-up is needed to assess the extent of the mortality reduction before firm conclusions can be reached on the long-term efficacy and cost-effectiveness of ovarian cancer screening," but Dr McConway pointed out that "further follow-up might possibly lead to the conclusion that, on balance, screening isn't worth it."

"The results are promising, but perhaps not all that promising," he said. "The multimodality screening missed 41% of the ovarian cancer cases. The authors report that the number of false-positive patients who were operated on was 'fewer than the upper acceptable limit' for multimodality screening, but there were still quite a few, and the complication rate in operations on false-positives is about 3%, which isn't huge, but needs to be take into consideration."

Another expert pointed out the same flaw in the study. Sir David Spiegelhalter, PhD, Winton Professor of the Public Understanding of Risk at the University of Cambridge, said: "The researchers unfortunately initially chose an inappropriate primary analysis. First, they assumed the intervention had a constant relative effect throughout all follow-up, whereas there is considerable delay before such screening might show benefit. Second, they included cases who turned out already to have ovarian cancer."

"The plots show clearly that there is no effect for the first 7 or so years, but after that, there is some evidence of a benefit, particularly if the cases who already had ovarian cancer at screening were left out," he said.

"Of course, this does not mean that a screening program is necessarily appropriate. The cost-effectiveness would need to be carefully assessed, taking into account long-term follow-up data," he explained.

The study was funded by the Medical Research Council, Cancer Research UK, and the Department of Health, with additional support from The Eve Appeal. Dr Jacobs reports that he is a coinventor of the ROCA and has a financial interest in Abcodia, which holds a license to the ROCA. Dr Menon reports a financial relationship with Abcodia. Dr Verheijen, Dr Zweemer, Dr Lu, Dr Fotopoulou, Dr McConway, and Dr Spiegelhalter have disclosed no relevant financial relationships.

Lancet. Published online December 17, 2015. Abstract, Comment

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