Early salpingectomy (TUbectomy) with delayed oophorectomy to improve QOL as alternative for risk-reducing salpingo-oophorectomy in BRCA 1/2 mutation carriers

 Full text - Study Protocol
Early salpingectomy (TUbectomy) with delayed oophorectomy to improve quality of life as alternative for risk-reducing salpingo-oophorectomy in BRCA1/2 mutation carriers (TUBA study): a prospective non-randomised multicentre study
 

Background

Risk-reducing salpingo-oophorectomy (RRSO) around the age of 40 is currently recommended to BRCA1/2 mutation carriers. This procedure decreases the elevated ovarian cancer risk by 80–96 % but it initiates premature menopause as well. The latter is associated with short-term and long-term morbidity, potentially affecting quality of life (QoL). Based on recent insights into the Fallopian tube as possible site of origin of serous ovarian carcinomas, an alternative preventive strategy has been put forward: early risk-reducing salpingectomy (RRS) and delayed oophorectomy (RRO). However, efficacy and safety of this alternative strategy have to be investigated. 

.......Although a randomised controlled trial would be the preferred study design, an earlier published feasibility study among healthcare professionals and germline BRCA1/2 mutation carriers showed that randomisation would be an insurmountable barrier for participation in a clinical study [51]. These women want to decide themselves on their risk-reducing strategy and it is therefore unlikely that they will participate in a randomised controlled trial. Taken this into account, a prospective non-randomised design seems the most appropriate, letting women the opportunity to decide for themselves......

Discussion

In this study protocol, we describe a prospective non-randomised multicentre trial in premenopausal BRCA mutation carriers. We compare the standard strategy to reduce ovarian cancer risk, i.e. RRSO at recommended age of 35–40 in BRCA1 and at recommended age of 40–45 in BRCA2 mutation carriers, with an innovative risk-reducing strategy. In this innovative strategy, early RRS is performed upon completion of childbearing and subsequent RRO is delayed for five years compared to the currently recommended age for the standard strategy. The primary outcome measure is menopause-related QoL. Secondary outcome measures include safety (cancer incidence and surgical complications), histopathological findings of surgery specimens, cardiovascular risk factors and cost-effectiveness.

Currently, there are two other ongoing studies investigating different aspects of salpingectomy in germline BRCA mutation carriers.

A research group from Texas investigates patient compliance with delayed oophorectomy after having undergone prophylactic salpingectomy (NCT01907789). They compare three regimens: ovarian cancer screening (3 years follow-up), prophylactic salpingectomy with delayed oophorectomy (4 years of follow-up including 1 year after oophorectomy) and risk-reducing salpingo-oophorectomy (1 year follow-up). QoL is measured as well. Like our study, they do not randomise. This study focuses on another endpoint, i.e. whether BRCA mutation carriers return for oophorectomy after earlier salpingectomy. Duration of follow-up is adjusted to this endpoint en is relatively short to assess the safety of RRS with delayed RRO as it comes to cancer incidence and non-cancer related morbidity. In our study, we focus on QoL, and several subdomains of QoL are measured as well. Nevertheless, our follow-up will not be ceased after QoL data completion, but will be prolonged to guarantee a close monitoring of cancer incidence and non-cancer related morbidity.

In a French study, BRCA mutation carriers who are reluctant to RRSO because of onset of premature menopause are offered a radical fimbriectomy as alternative (NCT01608074). Primary outcome is the number of pelvic serous carcinomas occurring between fimbriectomy and menopause. Secondary outcomes are perioperative morbidity, histopathologic findings of fimbriectomy specimens, incidence of breast cancer and the rate of secondary oophorectomy and associated morbidity.

In this study, fimbriectomy is only offered to women who refuse RRSO and RRS will in principle not be followed by RRO, while all women in our study eventually undergo RRO (current uptake of RRSO among BRCA mutation carriers is 95 % in the Netherlands). Furthermore, in this French study BRCA mutation carriers have to be older than 35 to be included. We include women from 25 years old, to optimize possible risk reduction by removing the Fallopian tubes as early as possible upon completion of childbearing. At last, the possible advantages of preservation of the ovaries for QoL are not evaluated in this fimbriectomy study, while this is the primary outcome in our study.

In conclusion, the current standard RRSO at age 35–40 (BRCA1) or 40–45 (BRCA2) is highly effective in reducing ovarian cancer incidence. However, consequent premature surgical menopause comes with short- and long-term noncancer-related morbidity and probably affects QoL. New insights in the origin of serous pelvic cancer put the Fallopian tube forward as target for alternative preventive surgery. The extent of the role of the Fallopian tubes in ovarian carcinogenesis remains uncertain. We expect that early salpingectomy with delayed oophorectomy is a reasonable alternative to preserve ovarian function towards the age of natural menopause without a significant increase in ovarian cancer incidence.