Cases and controls
The computer searches identified 255 women with a record of ovarian cancer; 43 were excluded. Of these, eight were aged <40 at diagnosis, 12 were suspected ovarian cancers only (six had other malignancies and six had benign ovarian disease), six had ovarian metastases, and six had recurrences of ovarian cancers initially diagnosed before 2000. Seven diagnoses had been made outside the study area, three had left the study area and their notes could not be retrieved, and one women had the wrong date of birth inadvertently recorded for the study, so her controls were 13 years younger, invalidating them from study. This left 212 cases, including 113 (53%) women who had died at the time of study but whose notes were retrievable. Each year we identified 12-26 eligible cases, until 2006 and 2007, when there were 44 and 52, respectively.
Histology results were available for 169 (80%) of the 212 cases, although 94 of these had no further descriptor other than carcinoma or adenocarcinoma. Of the 75 with the cell type specified, 66 (88%) were epithelial and nine (12%) non-epithelial. Thirteen women had borderline tumours. Staging data were available for 164 (77%), with 46 (28% of those with staging) FIGO stage I, seven (4%) stage II, 73 (45%) stage III, and 38 (23%) stage IV. Of the women aged over 70, 51 (81%) of the 63 with staging data were stages III or IV, whereas 60 (59%) of the 101 women aged 40-69 years with staging were stages III or IV (χ2 P=0.004).
There were 1239 controls who satisfied inclusion criteria, but 179 were ineligible: one had previously had ovarian cancer; 50 had undergone oophorectomy; 128 (10.8% of those eligible for study by every other criterion) had no consultations in the relevant one year period. Also, 76 (7.2%) controls had died at the time of study but their notes were retrievable.
Table 1 shows demographic details and the primary care consultations. The median age of cases was 67 years (interquartile range 58.5-77.5).
Table 1 Characteristics of women with ovarian cancer in primary care (cases) and matched controls. Figures are number (percentage) of women unless stated otherwise
We counted 99 variables associated with ovarian cancer at the P<0.1 level and entered these in a multivariable analysis. Table 2 shows the univariable analyses of those symptoms later found to be independently associated with a diagnosis of ovarian cancer in the multivariable analysis.
Table 2 Frequency of selected clinical features* in women with ovarian cancer in primary care (cases) and controls. Figures are number (percentage) of women
Seven symptoms remained in the final multivariable model (table 3). One antagonistic interaction was identified between abdominal distension and increased urinary frequency, meaning that when both symptoms were present, the overall effect is less than calculated by multiplying the odds ratios together. Of the symptoms shown in table 3, 181 (85%) women in cases and 164 (15%) controls had at least one. Three sensitivity analyses yielded negative results. Odds ratios were similar in those with and without histology, in those with stage I or II tumours compared with stage III and IV tumours, and in those cancers diagnosed before and after the introduction of the quality and outcomes framework (a payment scheme for UK general practitioners, which encouraged recording of cancer diagnoses).
Table 3 Multivariable analysis of symptoms of ovarian cancer in women in primary care
Multivariable analysis with data excluding the last 180 days identified early features of ovarian cancer (table 4). No interactions were found in this model.
Table 4 Multivariable analysis of symptoms, excluding final 180 days before diagnosis
Figure 1 shows the timings of presentations to primary care in relation to diagnosis for the four most common symptoms: abdominal distension, pain, or bloating and loss of appetite. These graphs compare the number of presentations to primary care between cases and controls, expressed as a monthly moving average.
Fig 1 Timing of symptom presentation to primary care in cases and controls. Time 0 is date of diagnosis in case. Y axes have different scales and show number of recordings of symptom each day per 1000 patients
Figure 2 shows positive predictive values for ovarian cancer for the symptoms shown to be independently associated in multivariable analysis individually, in combination with another symptom, and when the same symptom was reported a second time (shown on diagonal). The univariable positive predictive values and multivariable odds ratios (with 95% confidence intervals) were 2.5% (1.2% to 5.9%) and 240 (46 to 1200) for abdominal distension; 0.6% (0.3% to 1.0%) and 17 (6.1 to 50) for loss of appetite; 0.2% (0.1% to 0.3%) and 16 (5.6 to 48) for increased urinary frequency; 0.3% (0.2% to 0.3%) and 12 (6.1 to 22) for abdominal pain; and 0.3% (0.2% to 0.6%) and 5.3 (1.8 to 16) for abdominal bloating. For abdominal distension with loss of appetite, 20 cases but no controls had the combination; while strictly speaking undefined, the positive predictive value must logically be very high and so it has been set as >5%. For postmenopausal and rectal bleeding, the numbers were too small for calculation of positive predictive values in combinations, but the univariable positive predictive values were 0.5% (95% confidence interval 0.2% to 0.9%) for postmenopausal bleeding and 0.2% (0.1% to 0.4%) for rectal bleeding. All the symptoms in figure 2, except for urinary frequency, had higher positive predictive values in patients aged ≥70, reflecting the higher incidence of ovarian cancer in older women.
Fig 2 Positive predictive values (95% confidence intervals) for ovarian cancer for individual risk markers and for pairs of risk markers in combination (against background risk of 0.04%). Confidence intervals not calculated when any value was <5 (more ...)