Assessment of symptomatic women for early diagnosis of ovarian cancer: results from the prospective DOvE pilot project

Summary

Background

Around 90% of deaths from ovarian cancer are due to high-grade serous cancer (HGSC), which is frequently diagnosed at an advanced stage. Several cancer organisations made a joint recommendation that all women with specified symptoms of ovarian cancer should be tested with the aim of making an early diagnosis. In the Diagnosing Ovarian Cancer Early (DOvE) study we investigated whether open-access assessment would increase the rate of early-stage diagnosis.

Methods

Between May 1, 2008, and April 30, 2011, we enrolled women who were aged 50 years or older and who had symptoms of ovarian cancer. They were offered diagnostic testing with cancer antigen (CA-125) blood test and transvaginal ultrasonography (TVUS) at a central and a satellite open-access centre in Montreal, QC, Canada. We compared demographic characteristics of DOvE patients with those of women in the same age-group in the general population of the area, and compared indicators of disease burden with those in patients with ovarian cancer referred through the usual route to our gynaecological oncology clinic (clinic patients).

Findings

Among 1455 women assessed, 402 (27·6%) were in the highest-risk age group (≥65 years). 239 (16·4%) of 1455 required additional investigations. 22 gynaecological cancers were diagnosed, 11 (50%) of which were invasive ovarian cancers, including nine HGSC. The prevalence of invasive ovarian cancer, therefore, was one per 132 women (0·76%), which is ten times higher than that reported in screening studies. DOvE patients were significantly younger, more educated, and more frequently English speakers than were women in the general population. They also presented with less tumour burden than did the 75 clinic patients (median CA-125 concentration 72 U/mL, 95% CI 12–1190 vs 888 U/mL, 440–1936; p=0·010); Eight (73%) tumours were completely resectable in DOvE patients, compared with 33 (44%) in clinic patients (p=0·075). Seven (78%) of the HGSC in the DOvE group originated outside the ovaries and five were associated with only slightly raised CA-125 concentrations and minimal or no ovarian abnormalities on TVUS.

Interpretation

The proportion of HGSC that originated outside the ovaries in this study suggests that early diagnosis programmes should aim to identify low-volume disease rather than early-stage disease, and that diagnostic approaches should be modified accordingly. Although testing symptomatic women may result in earlier diagnosis of invasive ovarian cancer, large-scale implementation of this approach is premature.

Funding

Canadian Institutes of Health Research, Montreal General Hospital Foundation, Royal Victoria Hospital Foundation, Cedar's Cancer Institute, and La Fondation du Cancer Monique Malenfant-Pinizzotto.

Introduction

Ovarian cancer is the fifth leading cause of cancer-related death in women in developed countries¹ and has one of the highest ratios of incidence to death. Cure rates have not meaningfully improved in the past four decades.² Although there are many subtypes, high-grade serous cancer (HGSC) is the most important, as these tumours account for about 75% of all cases and 90% of all deaths due to ovarian cancer.³ As 5-year survival is 90% for patients with stage I disease at diagnosis, substantial investment has been put into identification of disease while it is confined to the ovary. Only 2% of HGSC cases are, however, diagnosed at stage I.⁴ In patients with advanced disease, the most important predictor of survival is complete surgical resection of all visible disease.⁵ Incompletely resected disease can be temporarily contained by chemotherapy, but most patients eventually succumb: 5-year survival for patients with completely resected stage III tumours is 65%, but for incompletely resected stage III tumours it is 20%.⁶ Thus, improved diagnostic strategies are needed.

Two diagnostic tests have been extensively assessed: measurement of cancer antigen (CA-125) concentrations in blood and transvaginal ultrasonography (TVUS).⁷ Both tests, however, have poor specificity, which, combined with the low prevalence of ovarian cancer in the general population, leads to high rates of false-positive results.⁷ Three randomised controlled trials on the feasibility of use and effectiveness of these tests in screening for ovarian cancer in postmenopausal women have collectively enrolled around 340 000 women and controls in three countries: the SCSOCS trial in Japan,⁸ the UKCTOCS study in the UK,⁹ and the PLCO study in the USA.¹⁰ Final results are available only for the PLCO study, but these indicate that screening did not reduce mortality from ovarian cancer and led to numerous unnecessary interventions.¹¹

Ovarian cancer used to be referred to as the silent killer because symptoms were thought not to present until late stages. Evidence now indicates that women diagnosed as having ovarian cancer, including those with early-stage disease, had symptoms that predated diagnosis by 3–36 months.12, 13, 14, 15, 16, 17 Owing to the vague and non-specific nature of these symptoms, however, women might delay seeking investigation.¹⁸ When women do present, symptoms are frequently attributed to benign gastrointestinal or urinary disorders.17, 19 In the hope of increasing the proportion of tumours diagnosed early, three major US cancer organisations, the American Cancer Society, the Gynecologic Cancer Foundation (now Foundation for Women's Cancer), and the Society of Gynecologic Oncologists, issued a joint advisory in June, 2007. They recommended that women who experience two ovarian cancer symptoms (among bloating, pelvic or abdominal pain, difficulty eating or early satiety, and increased urinary urgency or frequency) for 2 weeks or longer should undergo gynaecological assessment, TVUS, and measurement of CA-125.²⁰ 30 ovarian cancer alliances have since endorsed these recommendations,²¹ and the 2011 US National Comprehensive Cancer Network guidelines support a full diagnostic work-up for women with these symptoms.²² Studies that have so far reported that these symptoms are more frequent in patients diagnosed as having ovarian cancer than in controls, however, have been retrospective and, therefore, findings might have been affected by recall or ascertainment bias. Prospective studies are required to assess the usefulness of and the risks associated with widespread systematic testing of symptomatic women.

The Diagnosing Ovarian Cancer Early (DOvE) project was conceived with the objective of investigating whether prompt assessment of symptomatic women by CA-125 blood test and TVUS would increase the number of diagnoses of early-stage ovarian cancer compared with usual assessment, and whether predictive algorithms could be created for triage and testing of women. Because of the novelty of this design, we tested study feasibility in a pilot study of diagnostic testing, which we report here.