At the baseline screening round, a total of 566 surgeries were performed as diagnostic follow-up to positive screens, resulting in a diagnosis of 18 invasive cancers – the ratio of surgeries to invasive cancers was thus 31 to 1. Of the 18 cancers, 83% were Stage III or IV. Over three subsequent annual rounds of screening, there were 604 additional surgeries following positive screens and 42 more screen detected invasive cancers, giving a ratio of surgeries to cancers of 14 to 1; 67% of these cancers were stage III or above. Thus, during subsequent screening rounds, although the number of surgeries required to detect a cancer was halved from the baseline round, this ratio remained somewhat elevated, and the stage distribution of the detected cancers was only minimally improved. Over all four rounds of screening, the surgery to detected cancer ratio was 19.5 to 1, and 72% of screen detected cancers were late stage.
The above statistics reflect the complementary nature of the two screening tests being evaluated. The high rate of surgeries derives primarily from positive TVUs. At baseline, 94% of surgeries (biopsies) performed following positive screens were done in women with positive TVUs; this decreased marginally to around 80% for study years T1–T3. At baseline, the surgery to detected cancer ratio following a positive TVU was 44 to 1, as compared to 23 to 1 during subsequent screening rounds. In contrast, following a positive CA-125 test, the ratio of surgeries to cancers was about 4.5 to 1 at both the baseline and subsequent screening rounds. However, while the rate of “unnecessary” surgeries was much increased with TVU as compared to CA-125, TVU was also the test that detected the earlier stage cancers.
In the original report based on the baseline screening round results only, there were only 18 (screen detected) cancers, which limited the ability to perform sub-analyses. Now, with 60 screen detected cases, the pattern is clearer. The cases detected through TVU only (i.e., with normal CA-125), tended to be early stage; 71% of an admittedly small sample of 14 cases were stage I or II. Cases with elevated CA-125 however, regardless of whether they had an abnormal TVU or not, were primarily late stage; 89% of 27 cases with normal TVU and 79% of 19 cases with abnormal TVU. Of the 17 screen detected stage I/II cases, 10 (59%) were detected by TVU alone.
An interesting finding here was that the biopsy rate following a positive screen decreased from T0 to T1–T3. For TVU the decrease was from 40.6% at baseline to 17–24% at T1–T3, while for CA-125 the drop-off was from 15.6% at T0 to 9–12% at T1–T3. For CA-125, this decrease is explained by examining first positive screens over subsequent rounds. Among women with a first positive CA-125 screen at T1–T3, the biopsy rate was 14.8%, essentially equivalent to the T0 biopsy rate of 15.6%; thus first positive CA-125 tests at later rounds were followed up similarly to baseline round positives. In contrast, among repeat CA-125 positives, the average biopsy rate over T1–T3 was only 7%. For TVU however, even among the first positives at later rounds, the biopsy rate remained substantially lower (on average 23%) than the rate at baseline of 40.6%. The biopsy rate for repeat positive TVUs averaged 16%. We are currently investigating whether the specific findings on abnormal TVUs (e.g., cyst size, ovary size) may help explain the discrepancy in biopsy rates from baseline to subsequent rounds.
The large number of surgeries (primarily oophorectomies) prompted by a positive screen and not resulting in a cancer diagnosis here, 1,086 (or 3.5% of all women screened) should be seen in context of the background rate of oophorectomies in women of this age group. An essentially equivalent number (1,080) of oophorectomies (without a cancer finding) were performed on this cohort during this time period for reasons other than follow-up of a positive screen. Thus, while oophorectomies for other purposes were not un-common, this screening program utilizing CA-125 and TVU effectively doubled the oophorectomy rate in this cohort during the period of screening.
Several recent studies of screening with CA-125 and TVU had produced results generally similar to those observed here. In a trial of ovarian cancer screening in the U.K., Menon et al. utilized a sequential regimen of CA-125 followed (in some instances) by TVU [11
]. On the basis of CA-125 and age, women were assigned a risk score and those with high enough scores were then offered repeat CA-125 and/or TVU. Out of 6,532 women (median age 59.7) receiving an initial screen, 16 underwent surgery based on screening findings and 5 were diagnosed with ovarian malignancy. These numbers translate into a cancer yield of 7.7 per 10,000 women screened and a biopsy to detected cancer ratio of 3.2 to 1. Since all women in the U.K. study had to have elevated CA-125 to proceed to diagnostic follow-up, these figures are perhaps most appropriately compared to the corresponding PLCO results from women with a positive CA-125, which were a yield (at baseline) of 5.2 per 10,000 and a biopsy to detected case ratio of about 4.5 to 1. Thus the two studies demonstrated quite similar findings.
In a Japanese trial of CA-125 and TVU screening for ovarian cancer, among 41,688 women (median age 58) randomized to an intervention group, the yield of ovarian cancer was 3.1 per 10,000 women screened at the initial round and 3.8–7.4 per 10,000 women screened at later rounds (2 through 5) [12
]. This range for the yield in later rounds was quite comparable to that seen in PLCO (4.7 – 5.9), although the initial round yield was lower than the PLCO yield of 6.2. The overall ratio of surgeries to detected cancers was 33 to 1, a bit higher than the 19.5 to 1 ratio for PLCO. A total of 67% of the Japanese screen-detected cases (n=27) were stage I/II, compared to 29% in PLCO.
In conclusion, over three subsequent post-baseline annual screening rounds, the ratio of surgeries to detected cancers decreased somewhat from that observed in the baseline round, but still remained rather high at 14 to 1. As at baseline, the majority of screen detected cancers were stage III and above. TVU continued to account for most of the unnecessary surgeries in the subsequent rounds, but also for most of the early stage cancers. These data are consistent with the current guidelines of the U.S. Preventive Services Task Force that state that ovarian screening with CA-125 and TVU is not recommended. A determination on whether screening with these two modalities will reduce ovarian cancer mortality must await the final results of the PLCO Trial.