Download Riskreducing surgery for women at high risk of epithelial ovarian

DOI: 10.1111/tog.12107
2014;16:185–91
Review
The Obstetrician & Gynaecologist
http://onlinetog.org
Risk-reducing surgery for women at high risk of epithelial
ovarian cancer
Eve Maria Geraldine Gaughan
MRCPI
a,
BSc MB BCh BAO MRCOG MRCPI, *
Thomas Anthony Walsh
BSc MB BCh BAO MRCOG
b
a
Clinical Fellow in Gynaecology Oncology, Mater Miseracordiae Hospital, Eccles Street, Dublin 1, Ireland
Consultant Gynaecologist Oncologist with special interest in gynaecology oncology, Mater Miseracordiae Hospital, Eccles Street, Dublin 1, Ireland
*Correspondence: Eve Maria Geraldine Gaughan. Email: [email protected]
b
Accepted on 25 February 2014
Key content
The lifetime risk of ovarian cancer in the general population is 1.4%
but women with hereditary ovarian cancer syndromes have a lifetime
probability as high as 25–60% for developing epithelial ovarian cancer.
Screening has not been found to be associated with a statistically
significant reduction in mortality from ovarian cancer and cannot
be routinely recommended even for women at high risk. Serum
CA125 levels are only elevated in 50–60% of stage I ovarian cancers
and interval cancers may develop between screening visits.
Studies show a 4–20% risk of finding an occult malignancy at the
time of risk-reducing bilateral salpingo-oophorectomy.
Studies support the efficacy of risk-reducing bilateral
salpingo-oophorectomy in significantly reducing the risk of
gynaecological and breast cancer in women who carry BRCA1 or
BRCA2 mutations.
Women undergoing risk-reduction bilateral salpingooophorectomy should be counselled about the effects of early
menopause and the available management options including
hormone replacement therapy.
Learning objectives
To be able to identify those women at increased risk of
ovarian cancer.
To be able to appropriately counsel those at high risk of ovarian
cancer regarding modifiable risk factors, screening and the role of
risk-reducing surgery, including prophylactic bilateral
salpingo-oophorectomy and its alternatives such as tubal ligation
and salpingectomy.
To understand the limitations of current screening modalities for
the reduction of ovarian cancer risk.
Ethical issues
Ethical concerns exist pertaining to the performance of screening
modalities, which have not been found to significantly
reduce mortality from ovarian cancer and can cause harm
in terms of psychological and surgical morbidity from
false-positive results.
For those with a positive family history of ovarian cancer but no
genetic cancer syndrome, the discussion to perform risk-reducing
surgery should be balanced against the risk of surgical morbidity
and early menopause. Individual patient risk factors must be
considered in the decision-making process.
Keywords: bilateral salpingo-oophorectomy / BRCA gene / cancer /
epithelial ovarian cancer / risk-reducing surgery
Please cite this paper as: Gaughan EMG, Walsh TA. Risk-reducing surgery for women at high risk of epithelial ovarian cancer. The Obstetrician & Gynaecologist
2014;16:185–91.
Introduction
Ovarian cancer is the second most common gynaecological
malignancy and the most common cause of gynaecological
cancer death. The majority of ovarian tumours (90%) arise
from epithelial cells and the remainder are derived from
other ovarian cell types (germ cell and sex cord
stromal tumours).
The lifetime risk of ovarian cancer in the general
population is 1.4%. The median age at diagnosis is 57.1
Despite the good prognosis associated with early-stage
disease, overall 5-year survival is less than 45%. This poor
ª 2014 Royal College of Obstetricians and Gynaecologists
survival rate is largely due to the spread of cancer beyond the
ovary at time of diagnosis in 75% of patients.2
Risk factors
The strongest known risk factor is a family history of the
disease, which is present in about 10–15% of women with
ovarian cancer.3 The risk of ovarian cancer is increased when
the family history suggests a sporadic case but is substantially
greater when there is a hereditary cancer syndrome. Women
with a single family member affected by epithelial ovarian
cancer have a 4–5% risk, while those with two affected
185
Risk-reducing surgery for women at high risk of epithelial ovarian cancer
relatives have a 7% risk of developing the disease. In contrast,
women with hereditary ovarian cancer syndromes defined as
having at least two first-degree relatives with epithelial
ovarian cancer, have a lifetime probability as high as
13–50% for developing epithelial ovarian cancer.3
Breast ovarian cancer syndrome
Women with BRCA gene mutations have a greatly increased
risk of ovarian and breast cancer. The estimated risk of
ovarian cancer is 35–46% for BRCA1 mutation carriers and
13–23% for BRCA2 mutation carriers.3 BRCA mutations may
account for up to 90% of hereditary ovarian cancers.
Tumours in BRCA carriers are more likely to be invasive
serous adenocarcinomas when compared with non-BRCA
age-matched controls (odds ratio [OR] 1.84, 95% confidence
interval [CI] 1.21–2.79) and unlikely to be borderline
or mucinous.4
The stage at presentation of ovarian cancer is similar for
BRCA carriers and the general population – approximately
70% of patients present with stage III/IV disease.5 Ovarian
cancers in BRCA mutation carriers are more likely to be of
higher grade than ovarian cancers in age-matched controls.4
However, BRCA mutation carriers, particularly BRCA2
carriers, have a better prognosis than non-carriers. Studies
have shown that stage, grade and histology-adjusted 5-year
all-cause mortality was 45% in BRCA1 carriers versus 47% in
non-carriers (hazard ratio [HR] 0.73, 95% CI 0.64–0.84) and
36% versus 47% for BRCA2 carriers versus non-carriers (HR
0.49, 95% CI 0.39–0.61).6
Other high-risk genetic syndromes
Lynch syndrome, also called hereditary nonpolyposis
colorectal cancer (HNPCC), is associated with cancer
diagnosis at an early age and the development of multiple
cancer types, particularly colon and endometrial cancer.
Women with Lynch syndrome have a 3–14% lifetime risk of
ovarian cancer.7 HNPCC carriers account for 1% of ovarian
cancers.8 Peutz–Jeghers syndrome is associated with a 20%
risk of developing ovarian cancer but many of these are
non-epithelial sex cord stromal tumours.
Other risk factors
The risk of ovarian cancer appears to be decreased in
women with a history of pregnancy, use of the oral
contraceptive pill (OCP), breastfeeding, tubal ligation
and hysterectomy.
A history of ever using the OCP is associated with a
significant reduction in risk of developing ovarian cancer
(risk reduction [RR] 0.73, 95% CI 0.70–0.76).9 Larger
reductions in ovarian cancer risk occurred with increasing
duration of OCP use: RR decreased by about 20% for each
5 years of use; by 15 years the risk of ovarian cancer was
halved. Importantly, the protective effect persisted for
186
30 years after cessation of OCP use although the effect
attenuated over time. For women with 5 years’ use of OCP
the risk reduction in ovarian cancer within 10 years of
discontinuing OCPs versus 20–29 years after discontinuing
OCPs was 29% and 15%, respectively.9
Hysterectomy was associated with a 34% reduction in the
risk of ovarian cancer in a meta-analysis of 12 case–
control studies.10
Women who had undergone tubal ligation had a 34%
reduction in ovarian cancer risk in a meta-analysis of 13
case–control studies.11 In addition, a case–control study by
the Hereditary Ovarian Cancer Clinical Study Group12 found
that tubal ligation lowered the rate of ovarian cancer among
BRCA1 carriers by 60%, after adjustment for oral
contraception use, parity, history of breast cancer and
ethnic group. A history of both OCP use and tubal ligation
was even more protective, with 72% risk reduction. The
mechanism for this reduction is unknown but may coincide
with research that suggests that tubal neoplasia is a precursor
for serous ovarian cancer.13
Breastfeeding for a cumulative duration of more than
12 months compared with never breastfeeding is associated
with a statistically significant decrease in the risk of epithelial
ovarian cancer (OR 0.72, 95% CI 0.54–0.97).14
Current available data suggest that an association between
ovulation induction and ovarian cancer does not indicate
necessarily a causal effect. Infertility alone is an independent
risk factor. Nulliparous women may harbour a higher risk of
ovarian cancer irrespective of their use of fertility drugs. A
2013 Cochrane review by Rizzuto et al.15 concluded that
there was no convincing evidence of an increase in the risk
of invasive ovarian tumours with fertility drug treatment.
There may be an increased risk of borderline ovarian
tumours in subfertile women treated with in
vitro fertilisation.
The risk of ovarian cancer is slightly increased in women
with a history of endometriosis. The risk of malignant
transformation of ovarian endometriosis was estimated at
2.5%.16 Endometriosis-associated ovarian cancer appears to
occur in younger and nulliparous patients. These tumours
are well-differentiated low-stage carcinomas that have a
higher survival rate.
There is a small increased risk associated with polycystic
ovary syndrome (OR 2.52, 95% CI 1.08–5.89).17
Obesity appears to increase the ovarian cancer risk. A
systematic review reported a small, but statistically
significant, association between obesity and ovarian cancer
(OR 1.3, 95% CI 1.1–1.5).18
Screening
Screening for ovarian cancer with CA125 or ultrasound is
not recommended for premenopausal and postmenopausal
ª 2014 Royal College of Obstetricians and Gynaecologists
Gaughan and Walsh
women without a family history of ovarian cancer.19 The
predictive value of either test alone (less than 3%) yields
an unacceptably high rate of false-positive results and
attendant morbidity and costs. The combination of annual
CA125 testing with ultrasound did not decrease mortality
at 13-year follow-up in the Prostate, Lung, Colorectal and
Ovarian (PLCO) Cancer Screening Randomized Controlled
Trial20 and screening caused harm related to adverse
effects from surgery for false positive findings. The
continuing United Kingdom Collaborative Trial of
Ovarian Cancer Screening (UKC-TOCS)²¹ involves
202 638 low-risk postmenopausal women and is due to
report in 2015.
The potential of screening for any cancer is limited by
the clinical biology of the particular disease. At diagnosis,
the majority of patients with advanced ovarian cancer have
multiple nodules of cancer involving different peritoneal
sites.22 While it has generally been assumed that each
peritoneal nodule represents a metastasis from a primary
ovarian cancer, the disease might, in fact, be multifocal.
Hereditary ovarian cancer is frequently multifocal rather
than clonal.22,23 Anecdotal cases indicate that widespread
disease can be diagnosed 3 months after a negative
transvaginal ultrasound and normal serum CA125 values
have been obtained.24 As screening has not been associated
with a statistically significant reduction in mortality from
ovarian cancer, its use cannot be routinely recommended
even in women deemed at high risk. Interval cancers can
develop between screening visits and are often advanced at
presentation. Serum CA125 levels are only elevated in
50–60% of stage I ovarian cancers.25 For these reasons it is
not appropriate to use screening to reassure high-risk
women and it should only be offered in women
declining risk-reducing surgery, in the absence of a
better alternative.
Women at increased risk
It is important to differentiate those with a possible rare
familial cancer syndrome and those with the more common
presentation of an isolated family member with ovarian
cancer, without evidence of a hereditary pattern.
Lower-risk family history
Women with a family history but without evidence of a
hereditary pattern should be counselled about their
individual risk – considering age, parity and history of oral
contraceptive pill use – about the limited evidence for
effectiveness of screening and about the potential adverse
effects of screening. There is no evidence to support screening
in this group and decisions regarding screening and
risk-reducing surgery should be based on individualised
considerations involving the patient and clinician.
ª 2014 Royal College of Obstetricians and Gynaecologists
High-risk family history
Women with a suspected hereditary ovarian cancer syndrome
should be referred to a genetic counsellor for consideration of
testing for BRCA mutations or HNPCC if appropriate.
The United Kingdom Familial Ovarian Screening Study
(UK FOCCS) study,26 looking at the effectiveness of
screening in high-risk populations is due to report in 2015.
Even though evidence for screening effectiveness has not been
demonstrated to date, the decision to screen this patient
population is based on their very high lifetime risk of ovarian
cancer and is usually undertaken in women who decline
risk-reducing surgery.
For women declining risk-reducing surgery, some expert
groups have recommended screening with transvaginal
ultrasound plus CA125 assays every 6 months, starting at
the age of 35 years or 5–10 years earlier than the earliest age
of first diagnosis of ovarian cancer in the family. While this
may be a reasonable option, the evidence indicates limited
effectiveness of screening in this population, and clinicians
and patients should not be falsely reassured by negative
screening results. Most groups advise risk-reducing surgery
for this group by age 35–40 or when childbearing is
complete.27 See Table 1 for guidance on the management
for those at increased risk of ovarian cancer.
Chemoprevention
The combined oral contraceptive pill (COCP) has been
found to reduce the ovarian cancer risk in BRCA carriers. A
history of ever using the COCP in these women was
associated with significantly reduced risk of ovarian cancer
(RR 0.50, 95% CI 0.33–0.75).25 The protective effect
increased with longer duration of use. There has been
concern that COCP may increase the risk of breast cancer in
mutation carriers. Studies have shown an increased risk of
breast cancer with oral contraceptive formulations used
before 1975. However, studies have not shown a significantly
increased risk of breast cancer in users overall, or in the first
10 years after cessation of use of recent oral contraceptive
formulations.28 Given the available data, it has been
suggested that women with a hereditary ovarian cancer
syndrome who have not elected for risk-reducing surgery
and who are not trying to conceive should consider
COCP use.
Risk-reducing surgery
Lack of efficacy of ovarian cancer screening has prompted
many clinicians to recommend risk-reducing bilateral
salpingo-oophorectomy (rrBSO) at the completion of
childbearing rather than intensified screening for ovarian
cancer. Studies support the efficacy of rrBSO in significantly
reducing the risk of gynaecological and breast cancer in
187
Risk-reducing surgery for women at high risk of epithelial ovarian cancer
Table 1. Guidance for the management of women at increased risk of ovarian cancer
Risk of ovarian cancer
Suggested management
Increased risk
Positive family history, single member affected
not suggestive of a hereditary cancer syndrome
Risk of ovarian cancer: 4–5%
No evidence to support screening in this group
Could consider risk-reducing bilateral salpingo-oophorectomy
based on individualised considerations involving patient
and clinician
(General population risk: 1.7%)
High risk
Family history suggestive of a hereditary cancer
syndrome
Risk of ovarian cancer: 13–50%
BRCA1 has lifetime risk of ovarian cancer of 35–46%
BRCA2 has lifetime risk of ovarian cancer of 13–23%
HNPCC (hereditary nonpolyposis colorectal cancer, or
Lynch syndrome) has lifetime risk of ovarian cancer of 3–14%
women who carry BRCA1 or BRCA2 mutations. BSO in
premenopausal women with BRCA mutations has the
additional benefit of significantly reducing the risk of breast
cancer by 30 to 75%.29,30 As an example, in one study the
relative risk of ovarian/fallopian tube/peritoneal cancer after
rrBSO was 0.04% (95% CI 0.01–0.16) and in another study
the relative risk of breast/ovarian/fallopian tube/peritoneal
cancer was 0.25% (95% CI 0.08–0.74).29,30
Data regarding the finding of occult fallopian tube cancers
in women who have undergone rrBSO suggest that at least
some apparent ovarian cancers were initiated in the tubes.31
The possibility that the fallopian tubes are the primary site of
carcinogenesis in ovarian cancer has led to some experts
advocating salpingectomy at the time of hysterectomy in the
general population to reduce ovarian cancer risk.
Removal of healthy ovaries does not add significantly to
the operating time or immediate surgical complications of
hysterectomy, but may have significant implications for
short- and long-term health.
Lack of evidence from high-quality randomised clinical
trials limits the ability of surgeons and patients to make an
informed decision about the relative merits of ovarian
removal or conservation in those who are not at increased
inherited risk of ovarian cancer.
The postmenopausal ovaries are physiologically active and
continue to produce estradiol (at low levels) and
testosterone. The relative risks and benefits of
oophorectomy at the time of hysterectomy can be difficult
to estimate on an individualised basis.
188
No evidence to support screening in this group
Can offer screening to those who decline risk-reducing surgery
Offer risk-reducing surgery
Offer risk-reducing bilateral salpingo-oophorectomy after age
35 when childbearing is complete
Offer risk-reducing bilateral salpingo-oophorectomy after age 35.
May be delayed until age 45 because of later age of onset in this
group but this would mean losing the benefit of the associated
reduction in breast cancer risk
Offer risk-reducing bilateral salpingo-oophorectomy with concurrent
hysterectomy once family is complete because of risk of ovarian
and endometrial cancer
An observational study of nearly 30 000 women enrolled in
the Nurse’s Health study, (median follow-up of 24 years),
concluded that, ‘compared with ovarian conservation,
bilateral oophorectomy at the time of hysterectomy for
benign disease is associated with a decreased risk of breast
and ovarian cancer but an increased risk of all-cause
mortality, and fatal and nonfatal coronary heart disease’. At
no age was oophorectomy associated with increased survival,
but equally, it was not associated with a decreased survival in
women over the age of 55 at the time of hysterectomy
and oophorectomy.32
A further prospective cohort study of over 24 000 women,
with a shorter duration of follow-up (median 7.6 years),
concluded that, whilst oophorectomy at the time of
hysterectomy decreased the risk of ovarian cancer
compared to hysterectomy alone, it was not associated with
an increased risk of coronary heart disease, hip fracture
or death.33
Clearly there is conflicting evidence and therefore the
decision for oophorectomy must consider the individual
consequences for each woman with regard to her baseline risk
for developing breast and ovarian cancers, coronary artery
disease, osteoporosis, non-compliance and/or poor clinical
response to HRT. In postmenopausal women, there is no
consensus about whether ovaries should be removed or
retained and decisions should be made following patient
consultation on an individualised basis.
In view of the literature on ovarian carcinogenesis, Leblanc
et al.34 have proposed radical fimbriectomy for ovarian
ª 2014 Royal College of Obstetricians and Gynaecologists
Gaughan and Walsh
cancer risk reduction, for women who wish to retain their
fertility and ovarian function. Radical fimbriectomy consists
of removing all of the fallopian tube and the fimbrio-ovarian
junction. The safety and effectiveness of radical fibriectomy
for reducing ovarian carcinoma in the BRCA population has
not been assessed in clinical trials. Leblanc et al. proposed
this option for women who wish to retain their ovarian
function and fertility in preference to having no prophylactic
surgery at all.
It is important to remember that rrBSO is not completely
protective and BRCA carriers still have a risk of developing
primary peritoneal cancer (approximately 2% risk).35
All ovarian tissue should be removed. All ovarian adhesions
should be removed in their entirety to ensure no residual
ovarian cells remain.35 The ovarian artery and vein should be
clamped at least 2 cm proximal to the ovary, and preferably at
the pelvic brim to avoid leaving any ovarian tissue behind.41
The surgeon should remove as much of the fallopian tube as
possible but cornual resection does not appear to be necessary.
Although the intramural portion of the fallopian tube is
typically left behind after BSO, there have been no reports of
malignant transformation in the tubal remnant after this type
of surgery.42
Concurrent hysterectomy
Timing of surgery
This can be a difficult decision involving balancing the
procedure-related consequences of sterility and premature
menopause against the risk of ovarian and tubal cancer.
BRCA1 carriers develop ovarian cancer at a younger age than
BRCA2 carriers. Of women with a BRCA1 mutation and
ovarian cancer, 54% are diagnosed before the age of 50 years.
Diagnosis before the age of 40 is uncommon (2–3%) and
under the age of 30 is rare.36,37 Given that the age of onset is
usually over 40 it is appropriate to consider rrBSO for BRCA1
carriers after the age of 35 once childbearing is completed.
BRCA2 carriers reach a 2–3% incidence a decade later, by age
50 years and the average age at diagnosis is 60 years – similar
to the general population. Based on this difference in the
likely age of onset of ovarian cancer, BRCA2 carriers may
wish to delay their risk-reducing surgery but by doing this
they would not benefit from the reduction in breast cancer
afforded by salpingo-oophorectomy.38
Women considering rrBSO who have not completed
childbearing should be counselled about alternative
reproductive options including embryo cryopreservation.
Preservation of ovarian tissue is under investigation.
Surrogacy is an option for those undergoing
concurrent hysterectomy.
Preoperative evaluation
There is a 4–8% chance of detecting an occult malignancy at
the time of rrBSO. Over the age of 45 the risk rises to
approximately 20%.35,39–41 Pelvic ultrasound and CA125
level to evaluate for the presence of an ovarian malignancy
should therefore be performed prior to surgery. An
intraoperative finding of malignancy necessitates full
surgical staging and patients should be appropriately
counselled and consented about the possible need for
additional surgery.
Surgical procedure
The laparoscopic route is preferable to the open approach as it
is associated with less morbidity. The minimum surgery
required for risk reduction is bilateral salpingo-oophorectomy.
ª 2014 Royal College of Obstetricians and Gynaecologists
Hysterectomy may be performed at the same time as BSO
when there are other gynaecological indications. This increases
the associated morbidity and length of hospital stay.
Risk-reduction hysterectomy is beneficial in some groups,
for example women with Lynch syndrome who are at
increased risk of endometrial cancer (40–60% lifetime risk).43
Some BRCA carriers wish to take tamoxifen for
chemoprophylaxis of breast cancer. Tamoxifen use is
associated with an increased risk of endometrial pathology
and therefore these women may consider risk-reduction
hysterectomy at the time of BSO.
Women who wish to take unopposed estrogen therapy
may consider concurrent hysterectomy. Combined estrogen
and progestin therapy for those who require hormone
replacement therapy (HRT) is associated with a
significantly increased risk of breast cancer in
postmenopausal women, whereas no such association has
been noted with unopposed estrogen in this group.44,45 The
ability to generalise these data to premenopausal women who
undergo rrBSO is unclear.
Premature menopause
Women undergoing rrBSO should be counselled about the
effects of premature menopause and the available
management options. Menopausal effects include
menopausal symptoms such as hot flushes, sleep
disturbance, mood change and hair and skin changes.
Sexual-health-related effects include dyspareunia secondary
to vaginal atrophy and decreased libido. Long-term health
effects include osteoporosis, cardiovascular disease and
effects on cognitive and psychological function.
Surgical menopause differs from natural menopause in
that hormone levels drop abruptly and hormone production
ceases completely, as opposed to a gradual decline in
hormone level and continued production of androgens as
occurs with natural menopause. Women who undergo rrBSO
are typically younger than the average age of menopause of
51 and are therefore exposed to the detrimental effects of
hypoestrogenism for longer.
189
Risk-reducing surgery for women at high risk of epithelial ovarian cancer
The Scottish Intercollegiate Guidelines Network’s
guidelines on ovarian cancer46 have recommended giving
HRT after rrBSO up to the age of 50 as there is no decrease in
the benefit in terms of breast cancer risk reduction. Although
there is a small increase in the rate of breast cancer in women
on HRT, they are usually of a lower grade and HRT has no
impact on breast cancer mortality.47
The type of BRCA mutation may impact on HRT breast
cancer risk. Breast cancers in BRCA1 carriers are typically
negative for estrogen and progestin receptors, and thus are
potentially less likely to be influenced by hormones than the
breast cancers that develop in BRCA2 carriers which are
usually positive for these receptors.48
A shared decision-making process regarding the
management of menopausal symptoms and effects should
include discussion about non-hormonal options and the lack
of population-specific data for the use of HRT in BRCA
carriers after rrBSO. Factors that could possibly lower the
potential increased risk of breast cancer with HRT use
include limiting the duration of use until the age of 51 (the
average age of natural menopause), concurrent hysterectomy
to enable the use of unopposed estrogen and
prophylactic mastectomy.
Traditionally, a personal history of breast cancer has
been considered a contraindication to the use of HRT.
However, management of menopausal symptoms is an
important clinical problem. While most observational
studies have reported no increase in the risk of
recurrence with estrogen therapy, randomised clinical trial
data suggest that estrogen therapy may be associated with
excessive risk.49
Women who undergo rrBSO are at increased risk of
osteoporosis and should be counselled about osteoporosis
prevention, treatment and screening.
Vaginal atrophy can be treated with vaginal estrogen
preparations. Low-dose vaginal estrogens typically do not
raise the serum estrogen concentration above natural
menopausal levels. Studies of the use of vaginal estrogen in
women with a history of breast cancer have not shown an
increase in recurrence rates but data are limited.50
Non-hormonal preparations can be used as firstline
treatment but if these prove inadequate, vaginal estrogen is
a reasonable option.
Conclusion
Screening has not been found to be associated with a
statistically significant reduction in mortality from ovarian
cancer and cannot be routinely recommended even for
women at high risk. Studies support the efficacy of
risk-reducing
bilateral
salpingo-oophorectomy
in
significantly reducing the risk of gynaecological and breast
cancer in women who carry BRCA1 or BRCA2 mutations.
190
Decisions regarding screening and risk-reducing surgery
should be based on individualised considerations involving
the patient and clinician.
Disclosure of interests
The authors of this article have no conflict of interest
to disclose.
Contribution to authorship
TW came up with the idea to review the subject. EG
performed the literature search on the subject and compiled
the review with TW as supervisor. Both authors approved the
final version of this article.
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