Surgery to Reduce Ovarian Cancer Risk — One Step or Two?

Pam Harrison

March 25, 2019

HONOLULU — High-risk women who undergo prophylactic surgery to reduce ovarian cancer risk have few lingering worries about developing cancer in the future or regrets about their decision to undergo that surgery, suggest results from two studies.

The two studies, known as TUBA and WISP, were presented here at the Society of Gynecologic Oncology (SGO) Annual Meeting 2019.

Both studies were non-randomized, and had a similar design. They set out to compare quality of life endpoints in ovarian cancer risk mutation carriers who chose to undergo risk-reducing surgery, which was carried out either in one step, or two separate steps.

Some of these women underwent standard, risk-reducing salpingo-oophorectomy (RRSO, or removal of both the fallopian tubes and the ovaries in the same procedure). 

Others underwent two separate surgeries, initially having risk-reducing salpingectomy (fallopian tube removal only) followed some years later by delayed risk-reducing oophorectomy (both ovaries removed). This option is, at present, available only in clinical trials, researchers emphasized.  

"The reason high-risk women want to have their tubes removed first and delay removing the ovaries is to avoid 'surgical menopause' ", study investigator Karen Lu, MD, from the University of Texas MD Anderson Cancer Center in Houston told Medscape Medical News.

"But even when we give hormone replacement therapy (HRT) to women who have had their ovaries out for cancer prevention, they still do not feel ‘'normal,' as HRT can mitigate some of the symptoms [of the menopause] like hot flashes and night sweats, but not all," she added.

However, the desire to delay oophorectomy and remove only the fallopian tubes first is also supported by evidence implicating the fallopian tube as the tissue of origin for high-grade serous ovarian cancer, she added.

If, indeed, ovarian cancer risk is largely driven by malignant potential within the fallopian tubes, then delaying the removal of the ovaries helps delay the abrupt onset of menopause following their removal in relatively young women, she commented. 

Details of the TUBA Study

The primary endpoint of the Dutch TUBA study is an improvement in menopause-related quality of life, whereas the primary outcome in the US WISP (Women Choosing Surgical Prevention) study is the perception of sexual function following prophylactic surgery.

In the Dutch TUBA study, oophorectomy was postponed by 5 years after women had had their fallopian tubes removed between ages 40 to 45 if they were BRCA1 carriers and between ages 45 to 50 if they were BRCA2 carriers.

To date, a total of 384 women have been enrolled into the trial, with target enrollment set for 510 patients.

Women who are BRCA1 carriers are enrolled into the study between 25 to 40 years of age, and between 25 and 45 years if they are BRCA2 carriers, as noted by Miranda Steenbeek, MD, Radboud University Medical Center, Nijmegen, The Netherlands.

Preliminary pathological findings found that three patients in the RRSO group had either a visible or an occult malignant lesion on first surgery. 

Three malignant lesions were also found on first surgery in the salpingectomy arm, two of which were occult and one of which was visible, Steenbeek observed.

"We found that that there was a threefold level of cancer worry before surgery and there was an approximately equal decline at 3 months and 1 year after surgery," Steenbeek reported, There was no difference between the two treatment groups (ie, delayed ovary removal vs immediate ovary removal)," she added. Cancer worry was defined as the level of worry and fear a woman has that she will develop cancer in the future.

One year after surgery, rates of decision regret were again equivalent in both treatment groups, at 13% for the salpingectomy group followed by delayed oophorectomy vs 13.4% for the standard RRSO group.

As Steenbeek noted, these rates are very low, given that they reflect patients' feelings on a scale of 0 to 100, higher numbers denoting more regret. Decision regret as measured by a validated decision regret scale reflects the amount of regret a woman experiences after undergoing prophylactic surgery.

However, levels of regret were somewhat higher among women who could not or would not take HRT following standard RRSO, almost 19% of whom expressed regret a year after having the surgery.

Researchers suspect that these higher rates of regret are likely fueled by menopausal symptoms which, in the absence of HRT, are likely more severe than they are for those taking HRT.

"Our first results on quality of life are expected in 2020," Steenbeek noted.

"But based on these results so far, we cannot conclude that salpingectomy is a safe alternative to salpingo-oophorectomy and it is very important not to perform salpingectomy with delayed oophorectomy outside the safety and control of a clinical trial," she emphasized.

Details of the WISP Study

In the US WISP study, women with an inherited risk for ovarian cancer, conferred by a number of mutations in addition to BRCA1 and BRCA2, also chose between interval salpingectomy followed by delayed oophorectomy or the standard RRSO procedure.

As is true for the TUBA study, WISH trialists are planning to enroll some 80 additional patients into the trial. Early results are, however, available for 92 women enrolled in the interval salpingectomy group and 91 women enrolled in the RRSO group.

Women are between the ages of 30 to 50 on enrollment and are required to be premenopausal, Lu noted.

Somewhat different from the Dutch study, "our study requires women to have a normal CA125 and a normal transvaginal ultrasound within the last 6 months prior to surgery," Lu said.

In addition, "for all women, there was scripted counseling on the recommended age for oophorectomy for the prevention of ovarian cancer," she added.

The mean age of women in the interval salpingectomy, delayed oophorectomy (ISDO) group was 37.5 years, whereas the mean age in the RRSO group was significantly older at 40.9 years.

However, there were no differences in the mutational status between the 2 groups, with 87% of women in each group having a BRCA1 or BRCA2 mutation.

"No cancer was identified at initial surgery among the 92 women who underwent ISDO," Lu reported.

Among the 91 women who chose RRSO, one case of a high-grade serous tubal intraepithelial neoplasia was found in a woman with a PALB2 mutation.

"We also found that there was a significant decrease in cancer risk distress for both arms at 6 months after surgery, and there was no difference between the 2 groups," Lu observed.

In contrast, significantly more women in the RRSO group complained of menopausal symptoms at 6 months than those who had only their fallopian tubes removed.

These symptoms included hot flashes (P < .0001); night sweats (P = .008), and vaginal dryness (P = .004) — all of which were significantly more likely to occur in RRSO women than in ISDO patients. Women who underwent RRSO were also more likely to report weight gain after surgery than women who underwent ISDO (P = .02), Lu added. 

There were also significant differences in physical quality of life scores at 6 months in favor of the interval salpingectomy group, though not in mental health scores.

Perhaps the most interesting finding was the significant difference in decision regret scores between RRSO patients and those who underwent interval salpingectomy.

At 6 months, the decision regret score was 14.1 for those who had undergone RRSO compared with 8.7 for women who had undergone ISDO (P = .02).

Interestingly, regret was not mitigated by HRT, where even women who took HRT still had significant decision regret, Lu pointed out.

"We looked at a number of other factors that might predict decisional regret, and of all factors, we found only baseline depression scores were a significant, independent predictor of decision regret," Lu said.

As did Steenbeek, Lu cautioned that salpingectomies should not be done in high-risk women such as BRCA1 and BRCA2 carriers outside of a clinical trial, as there is currently no good evidence that that this procedure is safe to perform.

"If obstetrician/gynecologists are going to perform them, probably one of the most important things they can do is make sure that the pathologist does a very careful sectioning of the entire fallopian tube [on removal]," Lu stressed.

And if a microscopic lesion is found, "women need to go back and have a true cancer staging procedure, as we are requiring patients to do in our study," she added.

Both Trials Are Non-Randomized

Discussant Thomas Herzog, MD, professor of obstetrics & gynecology, University of Cincinnati Cancer Institute in Ohio, reiterated that both trials are predicated on the observation that the fallopian tube is the genesis for most serous ovarian cancers, and the fact that endogenous estrogens can improve quality of life in women who require prophylactic oophorectomy.

"We need to keep in mind that neither of these trials is randomized," Herzog cautioned. He also noted that results presented by Steenbeek and Lu are only interim results and that this should also be kept in mind when reviewing the findings.

"However, data will become more robust as researchers finish enrollment," Herzog noted.

"And while there are subtle differences between the trials, I think the studies are going to build upon one another and I'm very excited that the 2 groups are going to work together to determine the optimal approach to mitigate menopausal symptoms [in this patient population]," he suggested.

Steenbeek and Lu have disclosed no relevant financial relationships. Herzog has been on the scientific advisory board for AstraZeneca, Clovis, Caris, Genentech/Roche and Tesaro.

Society of Gynecologic Oncology (SGO) Annual Meeting 2019: Abstracts 2, 3. Presented March 17, 2019.

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