The NBOCC statements and recommendations about the management of women at high risk of ovarian cancer are based on a NBOCC systematic literature review39 of available evidence published between January 2003 and April 2010. Additional relevant articles, published after the completion of the review up until April 2010, have also been considered.
The NBOCC systematic review includes 49 published citations. Papers that included women at high risk or potentially high risk of ovarian cancer, including women with known BRCA1/2 mutations, women with Lynch Syndrome, and women with a strong family history of breast or ovarian cancer were identified. Most papers reported on populations with BRCA1 or BRCA2 mutations and most information was provided on risk-reducing salpingo-oophorectomy (RRSO).
Thirty-seven citations addressed the primary research questions:
- What is the effectiveness of risk-reducing strategies for women at high risk or potentially high risk of ovarian cancer?
- What is the effectiveness of surveillance strategies for women at high risk or potentially high risk of ovarian cancer?
- What are the psychological/psychosocial issues encountered by women at high risk or potentially high risk of ovarian cancer?
The remaining 12 citations addressed additional issues of interest including pathology of ovarian cancer in high risk women and relevance to risk-reducing surgical management, communication about risk including information needs of women and decision aid tools. Other topics identified were factors affecting decision making on risk-reducing strategies, uptake of risk-reducing strategies and cost-effectiveness of risk-reducing strategies.
Twenty-five studies were identified which evaluated the effects of risk-reducing salpingo-oophorectomy, including one meta-analysis.3 Three studies evaluated the association of oral contraceptive use and ovarian cancer risk and three studies evaluated the association of tubal ligation and ovarian cancer risk.
Risk-reducing salpingo-oophorectomy is a surgical procedure which includes the complete removal of both fallopian tubes and ovaries. RRSO provides a substantial reduction in the risk of developing ovarian and fallopian tube cancers in women with a BRCA1/2 gene mutation.3, 12
Benefits of risk-reducing surgery
Impact on survival
A large prospective cohort study by Domchek12 reported that in BRCA1/2 mutation carriers, RRSO reduced all-cause mortality by 60% (HR 0.40, 95% CI 0.26 to 0.61), ovarian cancer-specific mortality by 79% (HR 0.21, 95% CI 0.06 to 0.80) and breast cancer-specific mortality by 56% (HR 0.44, 95% CI 0.26 to 0.76). Modelling studies also suggest a survival benefit of RRSO,40-41 particularly when performed by age 40 and when combined with prophylactic mastectomy. Most of the other papers identified did not provide information about survival after RRSO.
Pooled results from three non-overlapping studies, which included 2840 participants, were used to provide a summary estimate for ovarian/fallopian tube cancer in BRCA1/2 mutation carriers. For BRCA1/2 mutation carriers treated with RRSO relative to those who did not receive this treatment the summary hazard ratio (HR) was 0.21 (95% CI 0.12 to 0.39) indicating a 79% reduction in gynaecologic cancer.3 The study by Domchek12 supported these findings for BRCA mutation carriers. Results were reported separately for women without or with prior breast cancer, each had reduced rates of ovarian cancer after RRSO (without prior breast cancer: HR 0.28 (95% CI 0.12 to 0.69); with prior breast cancer: HR 0.14 (95% CI 0.04 to 0.59).12
Risk-reducing salpingo-oophorectomy also reduces the risk of developing breast cancer in BRCA1/2 mutation carriers. Pooled results from three non-overlapping studies, which included 5703 participants, provided a summary estimate for breast cancer in BRCA1/2 mutation carriers. For BRCA1/2 mutation carriers treated with RRSO relative to those who did not receive this treatment, the summary hazard ratio (HR) was 0.49 (95% CI 0.37 to 0.65) indicating a 51% reduction in breast cancer.3 A prospective cohort published after this meta-analysis supported these results for BRCA mutation carriers with no prior breast cancer.12 The risk reduction may be more for BRCA2 mutation carriers than for BRCA1 mutation carriers.12 There was evidence for an age effect, with greater reduction in breast cancer risk for BRCA1 carriers who had RRSO before the age of 50, compared to after age 50.12 Since there is evidence that risk of ovarian cancer increases later in BRCA2 mutation carriers than for BRCA1,4 RRSO in BRCA2 mutation carriers could be delayed until age 45, but this may not provide the same degree of breast cancer risk reduction as RRSO at age 40.
Primary peritoneal carcinoma may occur despite risk-reducing salpingo-oophorectomy but is uncommon (≤1%).12, 18, 21-22
In women with Lynch Syndrome, there is an increased risk of cancer of the uterus and ovaries, among other cancers.5 Limited evidence is available about the efficacy of risk-reducing surgery to reduce the risk of ovarian cancer in women with Lynch Syndrome. A retrospective cohort of women with documented germ-line mutations associated with the Lynch Syndrome reported no cases of ovarian cancer after RRSO compared to 5% in the control group.42 Prophylactic surgery should be considered in these women from around the age of 35 in those who do not wish to preserve their fertility.42
Whilst there is evidence of reduced risk of ovarian cancer after tubal ligation in the general population, the association between tubal ligation and risk of ovarian cancer is not clear in high-risk women. One study has reported statistically significant reduction (over 50%) in ovarian cancer for BRCA1 mutation carriers who had undergone tubal ligation.30 Two other studies reported non-significant reductions in ovarian cancer risk after tubal ligation.31, 34
Occult cancers have been detected in the fallopian tubes and ovaries at RRSO. Rates of occult ovarian cancer detected at RRSO ranged from 0 to 17%.39 They were more often detected in BRCA1 mutation carriers and were often of fallopian tube origin. Occult cancers are likely more often detected in BRCA1 mutation carriers as cancers tend to develop at an earlier age in this population.19 The rate of occult cancer detected is also related to how the pathological examination is performed.19, 43 Domchek et al44 reported that women who had occult ovarian cancer at RRSO were older (mean age 51.7 vs. 46.6) and less likely to have used oral contraceptives (60% vs. 80%) than women who did not have occult ovarian cancer detected at RRSO. This study also reported that more occult ovarian cancers were diagnosed at an earlier stage compared to ovarian cancers detected outside the context of RRSO (37.5% stage I vs. 0% stage I, respectively, p=0.023).
Two cost-effectiveness studies evaluating preventive strategies for women with BRCA gene mutations both found that either RRSO alone or RRSO combined with prophylactic mastectomy were the most cost-effective for the study population. 29, 45 The Norwegian study confirmed that the significant reduction in risk of breast and ovarian cancer, prolonged survival and productivity gain from having both RRSO and prophylactic mastectomy produced savings that more than compensated for the up-front costs of the investigation and prophylactic therapy.45
Consequences of risk-reducing surgery
The procedures used for risk-reducing surgery in women at high risk are the same as those used for other indications. There is no reason to believe that the surgical complication rate for risk-reducing surgery for women with a gene mutation is different to that of the general population having similar surgery.13 A study by Schmeler13 in women with Lynch Syndrome did not identify any data to indicate a change in the surgical complication rate for this sub-group.
The main symptoms experienced after RRSO are those associated with surgically-induced menopause. Women with surgically-induced menopause more commonly report night sweats, sleep disturbance, hot flushes, and decreased libido and have significantly more severe vasomotor symptoms than women who go through natural menopause.24 Another study reported that within the RRSO group, those who had RRSO before age 50yrs had more palpitations than those with RRSO at ≥ 50yrs.46
Hormone replacement therapy (HRT) is effective in the management of menopausal symptoms following RRSO.47 Based on evidence from the systematic review there appears to be no increased risk of breast cancer in unaffected BRCA1/2 mutation carriers taking short-term HRT following RRSO performed before the age of 50.14 Further prospective studies may clarify this issue. Discussion about management of menopausal symptoms, including use of HRT, and psychosocial wellbeing should occur prior to risk-reducing surgery. Ongoing assessment of the effects of surgical menopause is required after surgery.
Long-term health effects
No studies were found reporting on the potential long-term health effects of RRSO on women at high risk of ovarian cancer. One review,9 outside the scope of the systematic review, identified several articles on the potential impacts on long-term health effects of RRSO on women at average risk of ovarian cancer. Studies showed women who had RRSO before age 45 and who had not received exogenous oestrogen up to age 45 had significantly higher cardiovascular mortality, compared to women who did have oestrogen following RRSO up until age 45 who showed no increase in mortality.48 In addition to adverse effects on cardiovascular and bone health, increased risk of Parkinson disease49 and dementia50 were also reported. While these studies are on the general population, they may provide possible insight into the effects of risk-reducing surgery on high risk women, however further research is required.
A number of papers described sexual activity and function for women after RRSO. Some papers reported that more women in RRSO groups had a decreased libido,24, 47 and it was consistently reported that women who underwent RRSO experienced more pain/discomfort during sexual activity than those in control groups.23, 47, 51
Four studies reported on psychological impact of RRSO. A range of scales to measure psychological impact were used, with levels of anxiety and depression most often reported. Inconsistent results were reported in the studies so the psychological impact of RRSO is uncertain.
For those who had RRSO, anxiety about developing ovarian cancer and breast cancer decreased substantially after surgery.24, 26
RRSO technique and pathology assessment
The specific technique of how RRSO was performed was often not provided in detail in the studies reporting effectiveness of RRSO. Where specific details were reported, the majority of patients underwent RRSO at the same time as total abdominal hysterectomy.13, 23, 52-53 In a retrospective study of risk-reducing surgery in Australian patients by Keily et al, 91% were assessed as having adequate surgery, whereas 23% were assessed as having adequate pathology (paraffin embedding of all removed ovarian and tubal tissue).27
Olivier et al (2004) reported a retrospective analysis on the outcomes of high-risk women who had undergone bilateral prophylactic oophorectomy (BPO) compared to women who had bilateral salpingo-oophorectomy (BSO).20 Occult cancers (3 fallopian tube; 2 ovarian) were only found in the women who had undergone BSO (8.6%, 5 out of 58), who were all BRCA1 mutation carriers. Three women from the BPO group went on to develop papillary peritoneal serous cancer within 45 months of follow-up after surgery.
Olivier et al (2005) also reported another retrospective analysis of women who had BPO compared to women who had additional bilateral salpingectomy (BPS) after BPO.54 The study reported three cases of peritoneal papillary serous cancer detected in the BPO alone group (mean follow-up of 66 months) compared to none in the group who had an additional BPS (mean follow-up 80 months) suggesting an additional risk reduction from BPS in BRCA1/2 carriers after having had BPO.54
Powell et al43 compared the detection of occult ovarian cancers depending on the level of adherence to an intensive RRSO protocol which included:
- bilateral salpingo-oophorectomy and removal of entire fallopian tube
- cytologic examination of peritoneal washings
- random peritoneal and omental biopsies
- serial sectioning of entire fallopian tubes and ovaries at 2mm intervals and microscopic examination of all sections.
The authors note that the rate of occult cancers detected in women who had full or partial adherence to the intensive protocol (17%, 7 out of 41) was considerably higher than in recent studies of BRCA mutation carriers whose RRSO procedures are routine (laparoscopic removal of the ovaries and fallopian tubes but without serial sectioning) with rates around 2.5%.43
Kiely et al reported that women attending a specialist gynaecologic oncologist for risk-reducing gynaecological surgery were more likely to have appropriate surgery and the surgical specimen more likely to have an adequate pathological examination.27
In addition to Powell43, Rabban55 described the use of serial sectioning of RRSO specimens to detect occult cancers. Rabban et al reported that there does not appear to be any diagnostic value in automatically performing multistep deeper level sections of RRSO specimens if the tissue is sectioned appropriately and if the specimen is sliced at intervals that are no more than 3mm thick.55 It was noted that pathological assessment should be performed by an experienced pathologist, and include all tissue from both tubes and ovaries, cut through at no more than 3mm intervals, processed and embedded with at least one section cut from each block.55 Informing the pathologist as to the reasons for the surgery is important in ensuring adequate assessment of the specimens. 27
Quality of life following RRSO
There is no consistent evidence of an overall impact on quality of life, either positive or negative, following RRSO.
In a study where women who had RRSO were compared to women who chose screening, more women who had RRSO were satisfied with their decision, 97% versus 82% respectively.26 For those who had RRSO, 86% would choose this procedure again and 63% would recommend it to a friend with familial risk of ovarian cancer.26 A systematic review on predictors of uptake of risk reduction and surveillance reported evidence of reduced anxiety in women following RRSO and also a high level of satisfaction with their decision. 25
There is evidence of reduced cancer worry in women, about both ovarian and breast cancer, following RRSO. Cancer worry is lowest in women who had both RRSO and prophylactic mastectomy.24, 26
There is evidence that women who have RRSO report more bodily pain at 12 months post-assessment than before the surgery.23 Women who have RRSO also report more discomfort (vaginal dryness and dyspareunia), less pleasure and satisfaction during sexual activity and more endocrine symptoms than women who have not undergone RRSO, and who participate in periodic gynaecologic screening only.23, 26
Factors affecting decision making on risk-reducing strategies
A systematic review on decision-making related to cancer risk-reducing strategies for women at high risk of hereditary breast and ovarian cancer, including 43 papers, reported factors that impact on decision making about RRSO. They included medical and physical factors, psychological factors, social context factors, BRCA1/2 mutation status and parity.56
Psychological factors of perceived cancer risk, and cancer related distress, anxiety and worry also appear to be influential in risk-reducing surgery decisions as well as the presence and number of relatives affected with cancer.56
Another systematic review, including 37 articles, 20 of which were prospective study design, reported that women’s attitude about risk-reducing surgery is a significant and useful predictor of undergoing risk-reducing surgery, as is age.25 They did not find a significant association between cancer worry and uptake of RRSO, although anxiety was significantly reduced after RRSO and women expressed a high level of satisfaction with their decision. 25
Use of a decision aid or shared decision-making, compared to a general educational pamphlet about risk-reducing strategies, reduces decisional conflict, improves knowledge and increases satisfaction with the decision. 36
A systematic review on risk communication including 28 articles reported that risk communication interventions achieved some benefits for users, mainly on cognitive outcomes such as risk perception and knowledge. 57
Oral contraceptive pill
Three primary studies were identified which assessed the impact of OCP use and ovarian cancer in women with BRCA 1/2 mutations.30-32 The studies on OCP use only report on risk of ovarian cancer and no information was provided on survival, adverse events or quality of life. Some papers provided risk estimates based on duration of OCP use.30-32 Studies indicated that use of OCP's is associated with a risk reduction in ovarian cancer of almost 50%, with longer duration of use (>3 years) associated with further reductions in risk,30-31 and in the general population, the risk reduction persists after cessation of the OCP.58
The cardiovascular risks for women in the general population taking the OCP are well known,59 however both the breast cancer33 and cardiovascular risk for women at high risk of ovarian cancer taking the OCP is uncertain.
The possible risks need to be balanced against the likely benefits of prescribing the OCP to women to reduce their risk of ovarian cancer.
Issues around surveillance
In December 2009, NBOCC published a position statement on surveillance of women at high or potentially high risk of ovarian cancer, which included evidence published up to January 2009.7 The current systematic review did not identify any new evidence that would alter the position statement.
NBOCC’s position statement on Surveillance of women at high or potentially high risk of ovarian cancer states:
- Ovarian cancer surveillance is not recommended for women at high or potentially high risk.
- Evidence shows that ultrasound or CA125, singly or in combination, is not effective at detecting early ovarian cancer.
The most effective risk-reducing strategy for ovarian cancer is bilateral salpingo-oophorectomy.7