30-year study suggests transvaginal ultrasound is a viable option for some high-risk women
Results of the 30-year prospective University of Kentucky Ovarian Cancer Screening Trial are adding to a body of evidence suggesting that an annual transvaginal ultrasound can detect early-stage ovarian cancer and improve survival rates for this patient population.
The cohort study by John van Nagell, MD, of the University of Kentucky Markey Cancer Center, and colleagues found that annual ultrasound screening of at-risk asymptomatic women was associated with early detection of lower-stage ovarian cancer and increased disease-free survival for types I and II epithelial ovarian cancer.
The study, published in Obstetrics & Gynecology, enrolled 46,101 women from January 1987 to June 2017 who met the eligibility criteria — women asymptomatic for ovarian cancer ages 50 or older and asymptomatic women ages 25 or older with a documented family history of ovarian cancer in at least one primary or secondary relative. Participants did not get genetic testing, but the women all completed a questionnaire that included medical history, surgical history, menopausal status, hormonal use, and family history of cancer.
The researchers documented a family history of ovarian cancer in 23.2% (20,195) of the participants and a family history of breast cancer in 43.8% (20,195). The women underwent 298,418 scans (mean of 6.5 scans per participant), with 246,275 scans (82.4%) visualizing one or both ovaries. Those women (699 or 1.5%) who had persisting ovarian tumors with transvaginal ultrasound underwent diagnostic surgery. This group was compared with 921 unscreened women with clinically detected epithelial ovarian cancer referred to the cancer center for treatment from 1995 to 2017.
The annual screenings found 71 invasive epithelial ovarian cancers and 17 epithelial ovarian tumors of low malignancy; of those with invasive epithelial ovarian cancer, 30 had stage I disease (42%), 15 had stage II (21%), 26 had stage III (37%), and no one had stage IV. These patients were followed from 9.2 months to 27 years. Looking at 5-, 10-, and 20-year disease-specific survival, the researchers found that the screened group had a significant survival benefit of 30% higher than the unscreened group.
“Sixty-three percent of women whose invasive ovarian cancer was detected by screening had stage I or II disease as opposed to 30% in unscreened women from the same geographic area diagnosed clinically during the same time period,” van Nagell and co-authors wrote. “That there was a substage shift within stage III in the screening group also is important, because there is a 5-year survival advantage of 20% in patients with stage IIIA compared with stage IIIC disease in the era of platinum+ taxane chemotherapy.”
Current Screening Guidelines
Survival for women with ovarian cancer, the leading cause of gynecologic cancer death in the U.S., remains dismally low. The U.S. Preventive Services Task Force (USPSTF) earlier this year reiterated their firm stance that average-risk, asymptomatic women should not be screened for ovarian cancer, citing the harms of screening — false-positive results, leading to unnecessary surgical interventions — and noting that research has not shown a reduction in mortality. The task force does recommend screening with CA-125 and transvaginal ultrasound in women who have genetic mutations and are considered very high-risk.
Asked for her perspective, Veena John, MD, system head of gynecologic cancer at Northwell Health Cancer Institute in New Hyde Park, N.Y., said she is not yet ready to change her clinical practice based on the trial by van Nagell et al., but noted that she follows the USPSTF’s recommendations that yearly screens are only for those women who carry genetic mutations. However, she added, “if the patient has a risk more than the average, it would benefit them to have sonograms.”
Still, she said that the issue of false positives is one of the main reasons for not jumping on the bandwagon of yearly screening considering the anxiety such testing can cause.
The University of Kentucky study acknowledged these concerns, particularly false-positive results from screening. The study authors noted that “in the United Kingdom Collaborative Trial of Ovarian Cancer Screening multimodal screening arm, only 15 of 488 screen-positive women with benign ovarian tumors at surgery (3.1%) experienced a postoperative complication, and 80% of these were minor.” In the Kentucky trial the authors noted that tumor removal via laparoscopy was their standard approach and if benign disease was detected, there was usually no further surgery.
“Surgical complications occurred in only 6.6% of these cases, and 97% of these complications were minor,” the researchers wrote.
Writing in an accompanying editorial, Sharon Robertson MD, MPH, and Jeffrey Peipert, MD, PhD, both of Indiana University School of Medicine in Indianapolis, called the effort of van Nagell and colleagues, “impressive,” but suggested caution interpreting the results for the general population. They pointed out several weaknesses of the study – the higher incidence of ovarian cancer in the study population vs the general population, the lack of genetic testing, and the fact that this was not a randomized controlled study.
Van Nagell, told the Reading Room that he does not dispute these observations and certainly agrees that a randomized controlled study would be warranted, but in a disease where the control group would be women who did not get screened and who would have to wait for clinical diagnosis, he asked, “Who would volunteer to be in that group?” He noted that women understand that ovarian cancer is considered a silent disease with at best, extremely subtle symptoms – for example, a feeling of fullness, abdominal bloating, a change in bowel habits, or urinary problems – and is often not found at its early stages.
Robertson and Peipert wrote that while the study did not reflect the general population they agreed with the authors’ conclusion that ultrasound screening in women at high risk for ovarian cancer may lead to earlier detection of the disease.
Van Nagell said he agreed with the recommendations from the British study for screening women with a lifetime risk of ovarian cancer of 3-10%, which includes women over age 50 or those over 25 with a family history of ovarian cancer.
John said that until there is an established screening guideline, it is important for physicians to understand the extremely subtle symptoms of ovarian cancer: “I tell my colleagues and those who refer patients to me to listen to the patients’ symptoms… please listen to them.” If transvaginal ultrasound screening or even prophylactic salpingo-oophorectomy is the recommended option, physicians and patients will need to discuss all the pros and cons of these options, she noted.
The Question of Mortality
In the Prostate, Lung, Colorectal, and Ovarian Trial conducted by Claire Zhu, PhD, and colleagues, the one trial often pointed to that dismisses routine screening for ovarian cancer, a reduction in mortality was not evident. “However, there was no standard evaluation algorithm for screen-detected ovarian tumors and no uniform treatment protocol for newly diagnosed ovarian cancers in this trial,” van Nagell and co-authors wrote. “As a result there was significant variation in the detection-treatment interval and type of treatment in both the screening and control arms of this trial.”
On the other hand, the U.K. trial did show an association with a reduction in mortality. And, with the University of Kentucky trial the association with reduced mortality was similar to the British study: “The 10-year ovarian cancer mortality was reduced in women receiving screening by 31% and produced 416 life years gained at a cost of $40,851 per life year gained.”
Van Nagell said he doesn’t dispute any of the opinions expressed by the USPSTF, the editorialists, or Veena John, but his ongoing work is erecting some pillars of care that may start to gain the attention of the wider community. While not calling for universal screening of women, establishing algorithms for screening protocols and surgeries certainly would help zero in on a devastating cancer, he said.
“We know if we can detect women with stage I or II cancer of the ovary, we can cure them,” van Nagell said. “We need to be defining a population that benefits from screening. Why on earth aren’t we focusing more on early detection methodology in at-risk women? Why on earth wouldn’t you want to focus on that risk group to try to detect cancer at an earlier and more curable stage?”