Best Practice & Research Clinical Obstetrics and Gynaecology 88 (2023) 102337

Contents lists available at ScienceDirect

Best Practice & Research Clinical

Obstetrics and Gynaecology
journal homepage: www.elsevier.com/locate/bpobgyn

Gynecological malignancies and obesity

Heather J. Agnew a, b, Sarah J. Kitson a, Emma J. Crosbie a, b, *
a
Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester,
UK
b
Department of Obstetrics and Gynaecology, Manchester University NHS Foundation Trust, St Mary's
Hospital, Manchester, UK

a b s t r a c t
Keywords:
Obesity The global pandemic of obesity has had a significant impact on
Endometrial neoplasms gynecological malignancies, most notably endometrial cancer. It
Ovarian neoplasms has resulted in worldwide increases in the incidence of endome-
Cardiovascular disease trial cancer and a change in patient demographics, resulting in
Risk more diagnoses than ever before being made in pre-menopausal
Mortality
women, who are often keen to pursue fertility-sparing treat-
ments. Obesity increases the risk of gynecological cancers by
creating a pro-carcinogenic environment of unopposed estrogen,
hyperinsulinemia, and chronic inflammation. It can present both a
diagnostic challenge and strongly influence management de-
cisions, including the practicalities of performing surgery, increase
anesthetic risks, and alter response rates to adjuvant and medical
therapies. Obesity may also influence endometrial cancer mortal-
ity and certainly contributes to poorer overall survival due to an
excess of deaths related to cardiovascular disease. Weight loss may
well, therefore, be the key to the prevention of gynecological
cancers and their recurrence.
© 2023 The Authors. Published by Elsevier Ltd. This is an open
access article under the CC BY license (http://creativecommons.
org/licenses/by/4.0/).

* Corresponding author. Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, 5th
Floor - Research, St Mary's Hospital, Manchester, M13 9WL, UK.
E-mail addresses: heather.agnew@postgrad.manchester.ac.uk (H.J. Agnew), sarah.kitson@manchester.ac.uk (S.J. Kitson),
emma.crosbie@manchester.ac.uk (E.J. Crosbie).

https://doi.org/10.1016/j.bpobgyn.2023.102337
1521-6934/© 2023 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://
creativecommons.org/licenses/by/4.0/).
H.J. Agnew, S.J. Kitson and E.J. Crosbie Best Practice & Research Clinical Obstetrics and Gynaecology 88 (2023) 102337

Endometrial cancer

Obesity and incidence of endometrial cancer

In high sociodemographic index (SDI) countries, endometrial cancer is now the 4th most common
cancer in women and the most common gynecological malignancy [1]. Annual diagnoses have reached
over 9700 in the UK and 65,000 in the USA [1,2]. Worldwide, this amounts to 417,000 new cases each
year. The countries with the highest rates of endometrial cancer are also those with high rates of
obesity (Fig. 1) [3].
In the UK, over the last 30 years there has been a 59% increase in the age-standardized incidence
rate of endometrial cancer [5] and, indeed, current projections suggest that endometrial cancer di-
agnoses could reach 11,500 by 2035 [1]. This increase is in part due to an aging population, with the
peak incidence rate of endometrial cancer occurring between 75 and 79 years of age [5]. There has,
however, also been a dramatic rise in the prevalence of risk factors for the disease, in particular the rate
of obesity, an occurrence not limited to high SDI nations. Obesity is now reaching pandemic pro-
portions, with 15% of the world's female population achieving a BMI (body mass index)
30 kg/m2, a
300% increase since 1975 [6]. All global regions, except for parts of sub-Saharan Africa and Asia, now
have more people with obesity than are underweight, dispelling the assumption that obesity is only a
disease of the wealthy [6,7]. The greatest increase in endometrial cancer cases has been observed in
low and middle-socio-demographic index nations as individuals there adopt a ‘Westernised’ lifestyle
[6,8].
This change in the prevalence of endometrial cancer risk factors has also resulted in increasing
numbers of women under the age of 50 years being diagnosed with the disease [8]. Not only is this
evident in the growing number of low-grade and early-stage tumors being diagnosed in women in
their 30s in the USA (2000e2017 women 30e34 years annual percentage change (APC) 2.6, 95%
confidence intervals (CI) 0.8e4.4, p ¼ 0.008 and women 35e39 years APC 2.6, 95%CI 1.2e4.1, p ¼ 0.001)
[9], but also in the proportion of cases occurring in women aged 25e49 years in countries with
traditionally lower incidence rates, such as New Zealand, Japan, India, and Costa Rica [3].

Obesity and endometrial cancer risk

Overweight and obesity are estimated to account for 41% of all endometrial cancers [10]. The
mechanisms by which excess adiposity contributes to endometrial carcinogenesis include inflamma-
tion, hyperinsulinemia and insulin resistance, and unopposed estrogen [11,12]. Obesity results in
increased bioavailability of estrogen through both the aromatization of androgens in excess peripheral
fat and through a reduction in sex hormone binding globulin (SHBG) in response to hyperinsulinemia
[12e15]. This is often not sufficiently countered by endogenous progesterone. This hyperestrogenic and
hyperinsulinaemic state, in conjunction with insulin resistance, also increases the bioavailability of
insulin-like growth factor 1 (IGF-1), which has a direct effect on the endometrium, stimulating prolif-
eration and activation of the pro-oncogenic Ras/Raf/mitogen-activated protein kinase (Ras-Raf-MAPK)
and phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin (PI3K-Akt-mTOR)
pathways (Fig. 2) [12,14,15]. Obesity is also associated with a chronic inflammatory state, creating a
favorable carcinogenic environment of pro-inflammatory cytokines, such as interleukin 6 and 8 (IL-6, IL-
8), which increase oxidative stress and induce DNA damage within the endometrium [12,15].
Endometrial cancer has been shown to have the strongest association with obesity of the 20 most
common tumor types [16]. Each 5 kg/m2 increase in BMI is associated with a 60% (95%CI, 50e68%)
increase in endometrial cancer risk, with potentially even stronger associations in women with the
highest BMIs [11,16]. The most comprehensive meta-analysis on the topic to date reported that women
with BMIs of 32 kg/m2 and 42 kg/m2 respectively appeared to have a 2.09 (95%CI 1.94e2.26) and 9.11
(95%CI 7.26e11.51) times risk of developing endometrial cancer compared with women with a BMI
<25 kg/m2 [11]. Positive associations have also been observed between endometrial cancer risk and
BMI in young adulthood, weight gain between early adulthood and middle age, waist circumference,
and waist-to-hip ratio, although it remains to be determined as to which measure of adiposity most
accurately predicts future endometrial cancer risk [17e19].

2
 H.J. Agnew, S.J. Kitson and E.J. Crosbie
Best Practice & Research Clinical Obstetrics and Gynaecology 88 (2023) 102337
3

Fig. 1. Comparison of global endometrial cancer incidence and prevalence of obesity in adult females. A) Worldwide incidence of endometrial cancer. B) Worldwide incidence of obesity. The
highest rates of obesity closely map to those countries with the greatest incidence of endometrial cancer [3,4].
H.J. Agnew, S.J. Kitson and E.J. Crosbie Best Practice & Research Clinical Obstetrics and Gynaecology 88 (2023) 102337

Fig. 1. (continued).

4
H.J. Agnew, S.J. Kitson and E.J. Crosbie Best Practice & Research Clinical Obstetrics and Gynaecology 88 (2023) 102337

Fig. 2. Obesity-induced carcinogenic pathways in the endometrium [14,15].

Besides the direct effect of obesity on endometrial carcinogenesis, excess adiposity also contributes
to an increased risk of endometrial cancer through its association with type 2 diabetes mellitus.
Currently, it is estimated that 32% of the population in the USA have type 2 diabetes (10.5% with
confirmed diagnoses) and a further 34.5% have pre-diabetic hyperglycemia [20]. Within the next 10
years, diagnoses in the UK are expected to reach 5.5 million, which will be an increase of 2 million cases
over a 15-year period [21]. The hyperinsulinemia induced by insulin resistance in type 2 diabetes is able
to drive endometrial proliferation and the accumulation of cancer-causing mutations within key on-
cogenes and tumor suppressor genes [22]. This effect appears to occur independently of its association
with obesity; however, as women with diabetes remain at a two-fold elevated risk of developing
endometrial cancer even once their BMI has been taken into account [23,24].

Obesity and endometrial cancer prevention

More than 60% of endometrial cancers are potentially believed to be preventable through risk factor
modification, including weight loss and changes in hormone usage [5,25,26]. Lack of physical activity
and a sedentary lifestyle contribute to and exacerbate both obesity and diabetes. Regular physical
activity has been shown to lower the risk of, and may protect against, endometrial cancer, through a
reduction in circulating insulin and estrogen, in addition to weight reduction and/or the prevention of
weight gain [13,18,27,28]. The amount of physical activity (50 MET-h/week (Metabolic Equivalent of
Task-hours per week) or 7 h of jogging) that must be undertaken to have a clinically significant impact
upon endometrial cancer risk is likely to be prohibitive, however, for the majority of women at greatest
risk of the disease [29].
There is evidence, albeit from observational studies only, that intentional weight loss of at least 5%
of body weight is associated with a significant reduction in endometrial cancer risk (HR 0.61, 95%CI
0.42e0.88) [30]. The effect appears to be linear, with increasing benefits seen in those able to lose the
greatest amount of weight. Sustaining diet-induced weight loss in the longer term, however, can be
challenging [31]. There have been no randomized controlled trials of drug-induced weight loss that

5
H.J. Agnew, S.J. Kitson and E.J. Crosbie Best Practice & Research Clinical Obstetrics and Gynaecology 88 (2023) 102337

have included endometrial cancer incidence as an outcome measure, but the use of agents such as
orlistat can be associated with a 7e10% reduction in body weight [32]. Surgically induced weight loss,
through bariatric surgery, is more significant and, importantly, durable than that achieved through
changes in diet and physical activity but is also life-changing [33]. Ward et al. retrospectively analyzed
data from over 850,000 women with obesity, noting that women who had previously undergone
bariatric surgery had a 71% (95%CI, 68e74%) lower incidence of endometrial cancer compared with
women with obesity who underwent no surgery [34]. The incidence was even lower in women who
had achieved a normal weight following their weight-loss procedure (RR 0.19, 95%CI 0.17e0.22) [34].
Similar findings were observed in the non-randomized Swedish Obese Subjects (SOS) trial, which
compared bariatric surgery with a primary care-based intervention, ranging from lifestyle advice to
usual care [35]. Endometrial cancer was the only female malignancy whose incidence was significantly
reduced following surgically induced weight loss (HR 0.51, 95%CI 0.35e0.89) [35]. Alongside weight
loss, bariatric surgery also leads to almost immediate reductions in circulating biomarkers of insulin
resistance as well as increases in sex hormone-binding globulin levels [36]. These metabolic changes
translate into a reduction in endometrial proliferation, as measured by Ki-67 expression (a marker of
proliferation), as well as changes in the immune microenvironment and histological resolution of the
endometrial cancer precursor, atypical endometrial hyperplasia [36,37]. Primary endometrial cancer
prevention is only one of the benefits of bariatric surgery, but this must be weighed up against the cost,
limited availability, and potential morbidity associated with undergoing the procedure.
Hormonal therapies can also be used to alter an individual's risk of endometrial cancer. The Eu-
ropean Prospective Investigation into Cancer and Nutrition (EPIC) cohort evaluated the effect of oral
contraceptives on endometrial cancer risk and found that prolonged use of hormonal therapy for 20
years or more translated to a 67% reduction in disease risk [25]. This protective effect has been shown
to persist for more than 30 years after cessation of oral contraceptives and is independent of BMI [38].
Having a BMI
35 kg/m2, however, is a relative contraindication to the use of the combined oral
contraceptive pill due to an increased risk of venous thromboembolic disease and an elevated risk of
myocardial infarction (MI) and stroke in individuals with associated cardiovascular risk factors [39].
The levonorgestrel-releasing intrauterine system (LNG-IUS) may, therefore, represent a more suitable
chemoprevention strategy for women with obesity. It delivers progestin directly to the endometrium
and its antiproliferative effect has been shown to reduce the risk of endometrial cancer by nearly 80%
(multivariable adjusted RR 0.22, 95%CI, 0.13e0.40) in women using it for contraception or the treat-
ment of heavy menstrual bleeding [40]. This occurs without the increased risk of breast cancer which
can be associated with prolonged oral contraceptive use [40]. The only study evaluating the LNG-IUS
for endometrial cancer prevention in women with obesity primarily reported on the feasibility and
acceptability of their study protocol, but did also note changes in endometrial morphology and a
reduction in Ki-67 and progesterone expression, even within the short 6-month duration of their trial
[41]. Longer-term studies are thus required to quantify the specific benefit of the LNG-IUS in women at
high risk of endometrial cancer.

Obesity and the diagnosis of endometrial cancer

Abnormal uterine bleeding is the presenting symptom in 90% of women with endometrial cancer,
most commonly reported as postmenopausal bleeding [42,43]. Endometrial cancer is diagnosed after
obtaining a relevant clinical history, performing an abdominal and vaginal examination, and per-
forming a series of investigations, which can include a pelvic ultrasound scan to assess the endometrial
thickness, endometrial biopsy, and hysteroscopic assessment of the uterine cavity [44]. The presence of
obesity poses a challenge at each stage of this diagnostic pathway.
Whilst clinicians and women are aware that postmenopausal bleeding can be the salient feature of
endometrial cancer, education around symptomatology in premenopausal women is currently lacking.
This is becoming an increasingly important issue as the number of women aged <45 years who are
being diagnosed with endometrial cancer rises. Current national guidelines do not support investi-
gation or referral on a suspected cancer pathway for women with abnormal uterine bleeding prior to
menopause and do not take into consideration the increased risk of endometrial cancer associated with
obesity [45]. However, a retrospective cohort study of 916 premenopausal women with abnormal

6
H.J. Agnew, S.J. Kitson and E.J. Crosbie Best Practice & Research Clinical Obstetrics and Gynaecology 88 (2023) 102337

uterine bleeding demonstrated that the incidence of endometrial cancer and complex hyperplasia was
nearly 5% in this group [46], similar to that in women with postmenopausal bleeding [44,47]. Even
more importantly, BMI was more predictive than age in determining whether an endometrial ab-
normality was present [46], supporting the inclusion of BMI in the diagnostic decision pathway. Pri-
mary care physicians and gynecologists must, therefore, have a high index of suspicion in
premenopausal women with raised BMI and abnormal bleeding.
Excess adiposity around the external genitalia and legs in women with obesity can limit access for a
thorough pelvic examination but can be ameliorated with the use of specialist speculums with added
length, such as a Winterton vaginal speculum. Hoists should be made available to transfer women with
limited mobility onto examination couches, which themselves need to have an adequate weight limit.
Experienced clinicians are required to ensure that an adequate endometrial biopsy is obtained with
minimal discomfort and may require women to be examined in the left lateral position. In a survey of
gynecological cancer screening undertaken in nearly 500 women with a BMI >25 kg/m2, weight was
found to be a significant barrier to accessing healthcare [48]. Of the women with a BMI >55 kg/m2
surveyed, 68% reported delaying seeking healthcare because of their weight, and 83% confirmed that
their weight prevented them from getting appropriate healthcare. Reasons included feeling dis-
respected, being weighed and receiving unsolicited advice, the negative attitude of healthcare pro-
viders, and that the equipment was too small to be functional [48]. Healthcare providers also reported
inadequate equipment, lack of training, and limited availability of resources to appropriately support
those with obesity [48,49]. Resources need, therefore, to be targeted at improving the experience of
women with obesity in primary care and the gynecology outpatient department.
Pelvic ultrasound is frequently used as a triage tool in abnormal uterine bleeding to determine the
need for an endometrial biopsy, with a widely established cut-off of 4 mm in postmenopausal women
[50]. The accuracy with which the double endometrial layer can be measured in the sagittal plane can
be hampered by body habitus, even when performed transvaginally.
Magnetic resonance imaging (MRI) is widely used to pre-operatively stage endometrial cancer,
allowing a more accurate assessment of the depth of myometrial invasion and the presence of
lymphadenopathy than computerized tomography (CT) [51,52]. However, there are weight and aper-
ture limits, which may prevent women with obesity from being able to safely fit inside routinely used
MRI scanners, as well as the potential for poorer image quality due to a large field of view and an
increased risk of thermal burns from contact with the bore [53]. Bariatric and open MRI machines are
available in some specialized centers to circumvent these issues.

Obesity and the treatment of endometrial cancer

The treatment of endometrial cancer predominately involves surgery with the potential addition of
radio- and chemotherapy. The presence of obesity impacts significantly each of these modalities (see
section on ovarian cancer for the impact of obesity on chemotherapy dosing).

Surgery

Over 70% of endometrial cancers are diagnosed with disease confined to the uterus (stages I and II)
[5], and, as such, they are amenable to primary surgical treatment. Operating on women with obesity
can be challenging due to restricted access to the pelvis and hindered maneuvering of instruments by
abdominal wall adiposity leading to prolonged surgical times and surgeon fatigue. The presence of
associated medical co-morbidities can also impact the safety of anesthesia, preventing a steep Tren-
delenburg position from being adopted and increasing the requirement for post-operative high-de-
pendency care to manage hypercapnia. The logistics of operating on women with obesity are more
complex generally, with the need for thorough pre-operative anesthetic assessment to allow detection
and optimization of conditions such as sleep apnoea, which could detrimentally affect the peri-
operative course [54]. Practically, ensuring the availability of adequate equipment is necessary for
the procedure such as longer instruments and/or longer laparoscopic ports, the need for a bed that can
tolerate the weight of the patient, and equipment to facilitate patient transfer while protecting the
theatre staff, e.g., a hover mattress [54]. Wound infections are more likely if an open procedure is

7
H.J. Agnew, S.J. Kitson and E.J. Crosbie Best Practice & Research Clinical Obstetrics and Gynaecology 88 (2023) 102337

undertaken [55]. Minimally invasive surgery is the preferred option due to its association with a
shorter hospital stay and lower intraoperative blood loss, with non-inferior oncological outcomes
[44,56]. Irrespective of surgical route, a large retrospective study of laparoscopic versus open surgery
for endometrial cancer demonstrated an increased rate of surgical site complications and adverse and
thromboembolic events in patients with obesity compared with those without [55]. Similar findings
were observed in Bouwman et al.,‘s institutional and systematic review, however, short-term post-
operative mortality was not significantly affected by BMI [57]. Whilst minimal access surgery is the
aim, the risk of conversion to open surgery is higher in women with obesity. In the prospective LAP2
trial (Laparoscopy Compared with Laparotomy for Comprehensive Surgical Staging of Uterine Cancer),
25.8% of 1682 patients undergoing an attempted laparoscopic hysterectomy for the treatment of
endometrial cancer required conversion to laparotomy to complete their procedure, with an 11% (95%
CI 9e13%, p < 0.0001) increase in the odds of conversion with each 1kg/m2 increase in BMI [58]. Over
57% of patients with a BMI
40 kg/m2 underwent conversion to laparotomy compared with 17.5% of
patients with a BMI of 25 kg/m2 [58]. The benefit of robotic surgery over straight stick laparoscopy is its
lower conversion rates in women with obesity, particularly those with a BMI
50 kg/m2, but with the
caveat of increased operating time and higher cost [59]. Some studies have revealed that women
undergoing robotic surgery had higher rates of lymphadenectomy compared with those having a
laparoscopic procedure, suggesting that more thorough staging is feasible even at very high BMIs
[59,60]. Not all patients will have access to robotic surgery; however, some women with obesity will,
therefore, be disadvantaged by the necessity of an open procedure where laparoscopic surgery is not
possible.

Radiotherapy

Radiotherapy, either as vaginal vault brachytherapy alone or in conjunction with external beam
radiotherapy, is used in both the primary and adjuvant treatment setting for endometrial cancer.
Radiotherapy is inferior to surgery for primary disease management, with recurrence rates of up to 18%,
but is a valid option in those unsuitable for surgical intervention. Combined external beam and
brachytherapy is associated with the best locoregional control and long-term outcomes but intra-
cavity therapy alone may be sufficient in early-stage, low-grade disease [61,62].
Radiotherapy can be particularly challenging in women with obesity due to greater daily shifts and
larger planning errors making it difficult to accurately target the radiotherapy beam. Resultantly,
healthy structures are at increased risk of inadvertent irradiation [63]. Image-guided and intensity-
modulated techniques allow for improved precision; however, even with these systematic errors
both the vertical and longitudinal direction increase as BMI rises. Set-up errors, i.e. the percentage of
fractions requiring a shift >7 mm in either the vertical, longitudinal, or lateral direction, have been
reported to be almost three times higher in women with a BMI
30 kg/m2 compared with women with
a lower BMI (BMI
30 kg/m2 27.9%, 14.7%, and 25.3%, respectively compared with BMI <30 kg/m2 11.2%,
4.8% and 6.4%, respectively) [64]. This is because of increased abdominal adiposity causing movement
of the skin and thus the tattoos which are used to guide treatment, as well as difficulties with applying
immobilization devices to this area of the body [63,64]. The accurate placement of intra-cavity
brachytherapy applicators can also be difficult at extremely high BMIs and may be further impacted
by the woman's fitness to undergo general anesthesia.

Progesterone therapy

Hormonal therapy is increasingly being used for young women wishing for fertility-sparing
endometrial cancer treatment and those with significant co-morbidities, including obesity, which
preclude surgery [44]. The use of intra-uterine progestin is associated with a reduction in the systemic
side effects observed with oral therapy and can stabilize or even reverse the neoplastic process within
the endometrium [65]. During this conservative management, regular biopsies and imaging are per-
formed every 3e6 months to detect progressive disease, thus allowing a hysterectomy to be performed
at the earliest opportunity if warranted [44]. A pathological response can take up to 6e12 months of
treatment; this may provide women with obesity with the time to achieve weight loss, either through a

8
H.J. Agnew, S.J. Kitson and E.J. Crosbie Best Practice & Research Clinical Obstetrics and Gynaecology 88 (2023) 102337

low-calorie diet or bariatric surgery, which, in itself, may make them more suitable candidates for
surgical intervention as well as, increasing the likelihood of disease regression with progesterone
treatment and optimizing any future fertility efforts [65]. Data from a prospective non-randomized
study of women with atypical endometrial hyperplasia and grade 1 endometrial cancer with mini-
mal myoinvasion treated with an LNG-IUS showed that women who lost >10% of their total body
weight were more likely to have a disease response compared with those who failed to lose any weight
(adjusted odds ratio 3.95; 95% CI 1.3, 12.5; P ¼ 0.02) [65]. In the recently published feMMe trial (A Phase
II Randomised Clinical Trial of Mirena®±Metformin in Patients with Early Stage Cancer of the Endo-
metrium), 67% of those randomized to intrauterine levonorgestrel in combination with a weight loss
intervention had complete pathological response at six months compared with 61% treated with in-
trauterine levonorgestrel alone [66]. This further highlights the importance of encouraging weight loss
even after an endometrial cancer diagnosis.

Obesity and endometrial cancer mortality and survival

Endometrial cancer is now the 7th most common cause of cancer death, accounting for 3% of all
female cancer deaths and 2400 deaths per year in the UK [5,43]. Globally, though the number of
endometrial cancer death is rising because of an increase in disease incidence, endometrial cancer
mortality rates have been in decline in response to improvements in treatment [67]. There remains,
however, a disparity in mortality rates between low- and high-SDI nations, where the mortality:
incidence ratios vary between 0.33 and 0.19, respectively [3]. This is especially important when
considering the fastest increase in endometrial cancer incidence has occurred in countries with the
most rapid economic growth, and where access to high-quality healthcare, including newer technology
such as robotic surgery, may lag behind the increased need for endometrial cancer treatments [3,67].
The ‘obesity paradox’ of endometrial cancer survival had previously suggested that women with
obesity were more likely to present with the low-grade and early-stage disease compared with women
with a normal BMI and that this contributed to the improved survival observed in this group [68]. More
recent data, however, refute this finding that obesity is a risk factor for increased all-cause and
endometrial cancer-specific mortality, with a 10% increase in BMI being associated with a 9.2% increase
in all-cause mortality (p ¼ 0.007) [68,69]. Within the NIH-AARP Diet and Health Study, women with
obesity and a history of endometrial cancer had higher all-cause and cancer-specific mortality at both 5
and 10 years after diagnosis than their normal weight counterparts [70]. Even in the context of high-
grade non-endometrioid endometrial cancer, increased visceral fat was found to be associated with
worse overall (HR 1.06, 95%CI 1.01e1.10, p ¼ 0.006) and disease-specific survival (HR 1.05, 95%CI
1.01e1.10; p ¼ 0.026) [71]. It is unclear, however, as to whether the difference in survival between
women with a BMI within the normal range and those with obesity is related to variation in approach
to endometrial cancer treatment, an adverse effect of obesity on the tumor microenvironment or
secondary to an increased risk of co-morbidities in women with obesity, most notably cardiovascular
disease.
This is an important consideration given that the majority of women are diagnosed with endo-
metrial cancer at an early stage, with good overall survival rates of 75.6% and 71.6% at 5 and 10 years,
respectively [5] and low recurrence rates of between 3 and 15% [72,73]. Data from the Surveillance,
Epidemiology, and End Result (SEER) database in the USA suggest that women with a history of
endometrial cancer have a 15.9-fold (95%CI 15.8e16.0) increased risk of death compared with women
without a history of the disease, even following treatment [74]. This is predominately due to an 8.8-fold
(95% CI 8.7e9.0) increase in the risk of death from cardiovascular disease [74]. Indeed, cardiovascular
disease is the leading cause of death in women previously diagnosed with endometrial cancer, with
women with the early-stage disease six times more likely to die from cardiovascular disease than from
endometrial cancer [75].
This dominance of cardiovascular disease in endometrial cancer survivorship is due to the presence
of several shared risk factors, which are frequently underdiagnosed and undertreated in this patient
group, in particular obesity [76]. Obesity predisposes an individual to develop cardiovascular disease
due to an increased risk of diabetes, hypertension, and hypercholesterolemia [77e79]. It is also,
however, an independent risk factor for coronary heart disease and stroke through the generation of a

9
H.J. Agnew, S.J. Kitson and E.J. Crosbie Best Practice & Research Clinical Obstetrics and Gynaecology 88 (2023) 102337

pro-thrombotic microenvironment, with increased activity of hemostatic factors and impaired fibri-
nolysis [78].
A recently updated Cochrane review assimilated the available evidence on the impact of in-
terventions aimed at inducing weight loss in endometrial cancer survivors on overall and endometrial
cancer-specific survival and cardiovascular event frequency [80]. It reported that there was insufficient
high-quality evidence to determine whether such interventions were beneficial, noting that they were
associated with little or no serious and life-threatening adverse events. A significant limitation of the
studies conducted to date, however, has been their small sample size, short follow-up time, and the
minimal weight loss actually achieved with any of the lifestyle and behavioral interventions studied.
What has become clear, however, is that the number of endometrial cancer survivors with obesity is
increasing and strategies aimed at improving the long-term health of these women are imperative. The
gynae-oncology clinic could represent the best place to address modifiable cardiovascular risk factors
at a time when individuals may be at their most susceptible to making lifestyle modifications.

Ovarian cancer

Obesity and ovarian cancer risk

The impact of obesity on ovarian cancer risk has been investigated in several large epidemiological
studies over the last 30 years, with inconsistent results [81,82]. More recently, evidence of a potential
effect appears to be limited to non-high-grade serous histotypes [82,83]. Data from 13,548 cases and
17,913 controls analyzed by the Ovarian Cancer Association Consortium suggested that for each 5 kg/
m2 increase in recent body mass index (BMI), there was a 13%, 19%, and 17% increase in the risk of low-
grade serous, mucinous and endometrioid ovarian cancer, respectively [82]. The absence of an asso-
ciation between obesity and high-grade serous ovarian cancer (HGSC) has been potentially attributed
to reverse causation, whereby women with advanced disease at diagnosis will often have lost weight
prior to presentation and may even have falsely elevated weight due to the presence of ascites. Evi-
dence from a Mendelian randomization study contradicts the above finding as it confirms that
genetically-predicted BMI remains associated with an increased risk of non-HGSC only (per 5 kg/m2
increase in BMI, non-HGSC OR 1.29, 95%CI 1.03e1.61, HGSC OR 1.06, 95%CI 0.88e1.27) [84]. Interest-
ingly, unlike endometrial cancer, neither waist nor hip circumference nor the relationship between the
two appears to influence ovarian cancer risk [85,86]. The presence of obesity at an early age, though,
does appear to have a stronger association with future ovarian cancer risk than BMI at diagnosis, but
again this effect is greatest for non-serous and premenopausal cases [87].
The same potential mechanisms of action that have been proposed to explain the association be-
tween obesity and endometrial cancer also apply to ovarian cancer, namely insulin resistance, adipose
tissue-induced aromatization of androgens into estrogen and inflammation, although evidence to
support these as dominant carcinogenic pathways in ovarian cancer are lacking.

Obesity and surgical morbidity

Approximately 60% of adults in the UK are overweight or obese and this is reflected in the current
ovarian cancer population [88,89]. Despite concern about the safety of undertaking maximal effort
debulking surgery in women with ovarian cancer and obesity, the available evidence has not
demonstrated a significantly increased peri-operative complication rate in this group compared with
normal-weight women, besides a greater risk of wound infection (OR 4.81, 95%CI 2.40e9.62) and a
clinically insignificant lengthening of hospital stay (mean difference 0.71 days, 95%CI 0.23e1.20) [89].
Rates of ileus, thromboembolic events, and pneumonia have not been found to differ according to BMI,
although data on cardiovascular morbidity was not collected in any of the studies included in the meta-
analysis. Short-term (30- and 90-day) mortality rates also do not appear to be elevated in obese women
undergoing ovarian cancer surgery. All of these studies may have significant risk of selection bias,
however, because they were conducted retrospectively and included only those women as their de-
nominator, who underwent surgery rather than all ovarian cancer diagnoses. They also included very
few women with class III obesity (BMI>40 kg/m2), increasing the size of the confidence intervals

10
H.J. Agnew, S.J. Kitson and E.J. Crosbie Best Practice & Research Clinical Obstetrics and Gynaecology 88 (2023) 102337

around estimates in this sub-group. These data do, however, support maximal effort surgery in women
with ovarian cancer irrespective of their BMI, with appropriate attention to peri-operative care,
including pre-habilitation, senior surgeons, and high dependency monitoring.

Obesity and chemotherapy

Chemotherapy dosing in ovarian (and endometrial) cancer is highly dependent on body weight and
how to approach the calculation of the required dose in women with obesity remains an active area of
debate. Paclitaxel is dosed based on body surface area (BSA), but because of concerns about excess
toxicity, doses are frequently capped at a BSA of 2 m2 or are calculated based on ideal rather than actual
body weight [90]. Creatinine clearance is used to determine carboplatin dosing but is estimated based
on glomerular filtration rate, itself heavily influenced by weight. As a result of concerns about toxicity
and the additional impact of obesity-related co-morbidities on this, women with obesity frequently
receive up to 45% lower doses of carboplatin and paclitaxel per kilogram of body weight than their
normal weight counterparts. The rates of neutropenia during chemotherapy and use of G-CSF have
been shown to be lower in women with obesity, potentially because dose reductions often take place
from the first cycle onwards rather than in response to low blood counts. There is a suggestion as well
that excess adipose tissue may affect the binding of chemotherapy drugs or their clearance through as
yet poorly understood differences in drug metabolism which could also make women with obesity less
susceptible to chemotherapy-associated toxicity [91].

Obesity and ovarian cancer survival

Bae et al. in their meta-analysis of 17 cohort studies showed no clear effect of obesity at diagnosis on
ovarian cancer survival (HR 1.11, 95%CI 0.97e1.27), although variable BMI cut-offs were used to define
obesity and the included observational studies frequently failed to adjust for potential confounding
variables, including stage and grade of disease and treatment received [92]. As discussed, under-
treatment of women with ovarian cancer and obesity does occur, even though when they receive
standard-of-care management, their outcomes are equivalent to women with normal body weight
[90].

Cervical, vulval, and vaginal cancer

Cervical cancer

Unlike endometrial and ovarian cancer, there is only limited evidence of a relationship between
obesity and cervical cancer. It is estimated that 99.8% of cervical cancers are caused by human papil-
lomavirus (HPV), however, other factors also contribute to the development of the disease as not all
HPV infections will progress to cervical cancer [93]. Women with a BMI
30 kg/m2 or who have gained
>10 kg in weight from age 18 do appear to be at elevated risk of cervical adenocarcinoma, with rates
approximately two-fold higher in this group compared with women with a normal BMI [94,95]. This
same association has not been shown between obesity and the more common squamous cell histotype.
In a study of nearly 500,000 women in the USA, the presence of obesity was associated with an
increase in cervical cancer mortality (RR 3.20, 95%CI 1.77e5.78, p ¼ 0.001) as well as increasing the risk
of cervical cancer [96]. A potential reason could be the reduced uptake of cervical cancer screening in
women with obesity, due to fears of embarrassment, a disrespectful attitude from healthcare providers,
and a lack of adequate equipment [48]. This is supported by data from a meta-analysis of 11 obser-
vational studies, which showed that compared with women with a BMI within the normal range, the
odds ratios for the uptake of cervical screening were 0.91 (0.80e1.03), 0.81 (0.70e0.93), 0.75
(0.64e0.88), and 0.62 (0.55e0.69) for women with a BMI 25e29.9 kg/m2, 30e34.9 kg/m2, 35e39.9 kg/
m2, and BMI
40 kg/m2 respectively [97]. This effect may be limited to those with the earliest stage
disease, though, as being underweight appears to have a greater adverse prognostic effect, especially
for those with locally advanced disease (overall survival HR 2.85 (95%CI 1.61e5.05) vs. 0.83 (95%CI
0.58e1.19) for BMI <18.5kg/m2 and
25kg/m2, respectively, disease-free survival HR 2.05 (95%CI

11
H.J. Agnew, S.J. Kitson and E.J. Crosbie Best Practice & Research Clinical Obstetrics and Gynaecology 88 (2023) 102337

1.17e3.57) vs. 0.84 (95%CI 0.61e1.16) for BMI <18.5kg/m2 and
25kg/m2, respectively) [98]. Potential
explanations include disease-induced cachexia and an increased number of complications in under-
weight women undergoing treatment.

Vulval and vaginal cancer

These rare cancers account for <1% of female malignancies in the UK and, like cervical cancer, are
frequently associated with HPV infections [99,100]. Due to their rarity, there is very little epidemio-
logical data available for analysis of other disease co-factors. A recent systematic review reported an
association between vulval cancer, metabolic syndrome (diabetes, hypertension, and central obesity)
and increased BMI (OR 1.7e2.9), albeit based on a handful of small case-control studies [101]. This
relationship may be ascribed to obesity-induced low-level chronic inflammation, hyperinsulinemia,
and altered sex-steroid hormone metabolism, similar to the situation with other gynecological ma-
lignancies, but direct evidence of a mechanistic effect in vulval cancer is lacking [101]. The AGO-CaRE-1
study was designed to analyze treatment patterns and prognostic factors in vulval cancer. Despite
undergoing higher rates of vulvectomy and equivalent groin node staging and adjuvant treatment,
women with a BMI
30 kg/m2 had an increased rate of disease recurrence compared with women
without obesity (BMI
30 kg/m2 43.3% vs BMI <30 kg/m2 28.2%, p < 0.001), mainly due to an elevated
risk of local recurrence (BMI
30 kg/m2 33.3% vs BMI <30 kg/m2 18.5%, p < 0.001). The time to
recurrence was reduced by nearly half (BMI
30 kg/m2 43.8 months, 95%CI 23.3e64.3, vs BMI <30 kg/
m2 102.3 months, 95%CI 72.6e131.9), p ¼ 0.001), although there was no difference in median overall
survival between the two groups [102]. These data may be suggestive of less radical excision margins in
women with obesity due to restricted perineal access, but this has not yet been formally demonstrated.
Increased surveillance during follow-up to detect early recurrence may, however, be warranted in this
group.

Summary

The rising incidence of endometrial cancer, with the development of over 400,000 cases worldwide
each year, can be directly attributed to the increasing number of women with obesity. Up to two-thirds
of cases are potentially preventable with lifestyle modification; specifically, weight loss, increasing
physical activity, and change in hormone usage. Treating women with gynecological malignancies and
obesity can prove challenging, as surgery requires intense pre-operative planning, and specialist
equipment and has increased complications, particularly if open surgery is necessary. Chemotherapy
and radiotherapy dosing and delivery can also be more demanding in the presence of obesity.
For endometrial cancer, obesity increases both overall and cancer-specific mortality. In patients
with low-grade and early-stage disease, women are more likely to die from a heart attack or stroke
than endometrial cancer. This is perhaps not surprising given the presence of shared risk factors for the
two diseases, in particular obesity.
Although evidence regarding obesity and cervical, vulval, and vaginal cancer is limited, there is clear
evidence that the uptake of screening is lower in women with a BMI >30 kg/m2 and that this is due to
several potentially modifiable factors such as equipment availability and the training and attitude of
healthcare professionals. It is imperative to work with patients to create a space that minimizes
embarrassment and allows both cancer screening and the investigation of concerning gynecological
symptoms to be performed.
Without intervention, the global obesity pandemic will continue to have a significant impact on
gynecological malignancies.

Source of funding

HJA is supported by the Manchester University NHS Foundation Trust Clinical Research Fellowship.
SJK is funded by the National Institute for Health and Care Research as an academic clinical lecturer and
is in receipt of a Wellbeing of Women postdoctoral research fellowship PRF 101. EJC is supported by an

12
H.J. Agnew, S.J. Kitson and E.J. Crosbie Best Practice & Research Clinical Obstetrics and Gynaecology 88 (2023) 102337

NIHR Advanced Fellowship (NIHR300650) and the NIHR Manchester Biomedical Research Centre (IS-
BRC-1215-20007).
The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the
Department of Health.

Practice points

 A high index of suspicion is required in both primary care and outpatient gynecology de-
partments when evaluating premenopausal women with abnormal bleeding patterns and
obesity.
 Management of women with gynecological malignancy and obesity should include a dis-
cussion of the increased risks of treatment, including the potential surgical complications and
impact on alternative/adjuvant therapies; however, this should be individualized to each
patient and done in such a manner as not to alienate or attribute a feeling of blame.
 Progesterone therapy can be used successfully to stabilize or cause regression of early
endometrial cancers, allowing for fertility preservation or weight loss, but requires careful
monitoring with regular biopsies and scans
 Endometrial cancer patients should receive a cardiovascular risk assessment as part of their
ongoing treatment, which should include weight management strategies such as diet, ex-
ercise, and referral to bariatric surgery where appropriate.
 Ovarian cancer surgery can be extensive, and obesity should not preclude a patient from
maximal efforts of cytoreduction but will require increased pre-operative planning.
 Efforts should be made to increase the uptake of cancer screening in women with obesity
through education of both the patient and healthcare professional to tackle barriers that exist
in current practice

Research agenda

 Diagnostic Pathway in premenopausal women

 Trials of weight loss with endometrial cancer incidence as an outcome
 A long-term study on the use of the LNG-IUS in endometrial cancer prevention
 Long-term studies detailing the impact of weight loss interventions on endometrial cancer
survival including the effect of surgical weight loss

Declaration of competing interest

The authors declare no conflicts of interest.

References

[1] Cancer Research UK. Cancer incidence for common cancers [cited 2022 November 25th]. Available from: https://www.
cancerresearchuk.org/health-professional/cancer-statistics/incidence/common-cancers-compared#heading-Two.
[2] National Cancer Institute. Cancer Stat Facts: Uterine Cancer [cited 2022 Novemebr 25th]. Available from: https://seer.
cancer.gov/statfacts/html/corp.html.
[3] Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN
estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA A Cancer J Clin 2021;71(3):209e49.
[4] Ritchie H, Roser M. Obesity published online at ourworldindata.org2017 [Available from: https://ourworldindata.org/
obesity.
[5] Cancer Research UK. Uterine cancer statistics [cited 2022 December 16th]. Available from: https://www.
cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/uterine-cancer#heading-Three.
[6] World Health Organisation (WHO). Fact sheets: obesity and overweight [Available from:. 2021. https://www.who.int/en/
news-room/fact-sheets/detail/obesity-and-overweight.
[7] Abarca-Go
mez L, Abdeen ZA, Hamid ZA, Abu-Rmeileh NM, Acosta-Cazares B, Acuin C, et al. Worldwide trends in body-
mass index, underweight, overweight, and obesity from 1975 to 2016: a pooled analysis of 2416 population-based
measurement studies in 128$9 million children, adolescents, and adults. Lancet 2017;390(10113):2627e42.

13
H.J. Agnew, S.J. Kitson and E.J. Crosbie Best Practice & Research Clinical Obstetrics and Gynaecology 88 (2023) 102337

[8] Lortet-Tieulent J, Ferlay J, Bray F, Jemal A. International patterns and trends in endometrial cancer incidence, 1978e2013.
JNCI. J Natl Cancer Inst 2018;110(4):354e61.
[9] Matsuo K, Mandelbaum R, Matsuzaki S, Klar M, Roman L, Wright J. Ovarian conservation for young women with early-
stage, low-grade endometrial cancer: a 2-step schema. Am J Obstet Gynecol 2021;224(6):574e84.
[10] Bhaskaran K, Douglas I, Forbes H, Dos-Santos-Silva I, Leon DA, Smeeth L. Body-mass index and risk of 22 specific cancers:
a population-based cohort study of 5$24 million UK adults. Lancet 2014;384(9945):755e65.
[11] Crosbie EJ, Zwahlen M, Kitchener HC, Egger M, Renehan AG. Body mass index, hormone replacement therapy, and
endometrial cancer risk: a meta-analysis. Cancer Epidemiol Biomark Prev 2010;19(12):3119e30.
[12] Mackintosh M, Crosbie E. Obesity-driven endometrial cancer: is weight loss the answer? BJOG An Int J Obstet Gynaecol
2013;120(7):791e4.
[13] Kaaks R, Lukanova A, Kurzer MS. Obesity, endogenous hormones, and endometrial cancer risk: a synthetic review. Cancer
Epidemiol Biomark Prev 2002;11:1531e43.
[14] Hazelwood E, Sanderson E, Tan VY, Ruth KS, Frayling TM, Dimou N, et al. Identifying molecular mediators of the rela-
tionship between body mass index and endometrial cancer risk: a Mendelian randomization analysis. BMC Med 2022;
20(1):125.
[15] Crosbie EJ, Kitson SJ, McAlpine JN, Mukhopadhyay A, Powell ME, Singh N. Endometrial cancer. Lancet 2022;399(10333):
1412e28.
[16] Renehan AG, Tyson M, Egger M, Heller RF, Zwahlen M. Body-mass index and incidence of cancer: a systematic review and
meta-analysis of prospective observational studies. Lancet 2008;371(9612):569e78.
[17] Aune D, Navarro Rosenblatt DA, Chan DSM, Vingeliene S, Abar L, Vieira AR, et al. Anthropometric factors and endometrial
cancer risk: a systematic review and doseeresponse meta-analysis of prospective studies. Ann Oncol 2015;26(8):
1635e48.
[18] Raglan O, Kalliala I, Markozannes G, Cividini S, Gunter MJ, Nautiyal J, et al. Risk factors for endometrial cancer: an
umbrella review of the literature. Int J Cancer 2019;145(7):1719e30.
[19] Kitson SJ, Evans DG, Crosbie EJ. Identifying high-risk women for endometrial cancer prevention strategies: proposal of an
endometrial cancer risk prediction model. Cancer Prev Res 2017;10(1):1e13.
[20] Centers for Disease Control and Prevention. National diabetes statistics report. In: Centers for disease control and pre-
vention UDoHaHS; 2017.
[21] Diabetes UK. Diabetes statistics [Available from:. 2020. https://www.diabetes.org.uk/professionals/position-statements-
reports/statistics.
[22] Anastasi E, Filardi T, Tartaglione S, Lenzi A, Angeloni A, Morano S. Linking type 2 diabetes and gynecological cancer: an
introductory overview. Clin Chem Lab Med 2018;56(9):1413e25.
[23] Friberg E, Orsini N, Mantzoros CS, Wolk A. Diabetes mellitus and risk of endometrial cancer: a meta-analysis. Dia-
betologia 2007;50(7):1365e74.
[24] Saed L, Varse F, Baradaran HR, Moradi Y, Khateri S, Friberg E, et al. The effect of diabetes on the risk of endometrial
Cancer: an updated a systematic review and meta-analysis. BMC Cancer 2019;19(1).
[25] Fortner RT, Hüsing A, Dossus L, Tjønneland A, Overvad K, Dahm CC, et al. Theoretical potential for endometrial can-
cerprevention through primary risk factor modification: estimates from the EPIC cohort. Int J Cancer 2020;147(5):
1325e33.
[26] Kabat GC, Matthews CE, Kamensky V, Hollenbeck AR, Rohan TE. Adherence to cancer prevention guidelines and cancer
incidence, cancer mortality, and total mortality: a prospective cohort study. Am J Clin Nutr 2015;101(3):558e69.
[27] World Cancer Research Fund International, American Institute for Cancer Research. Diet, nutrition, physical activity and
endometrial cancer [Available from. 2018. https://www.wcrf.org/dietandcancer/endometrial-cancer/.
[28] Schmid D, Behrens G, Keimling M, Jochem C, Ricci C, Leitzmann M. A systematic review and meta-analysis of physical
activity and endometrial cancer risk. Eur J Epidemiol 2015;30(5):397e412.
[29] Kitson SJ, Aurangzeb O, Parvaiz J, Lophatananon A, Muir KR, Crosbie EJ. Quantifying the effect of physical activity on
endometrial cancer risk. Cancer Prev Res 2022;15(9):605e21.
[30] Luo J, Hendryx M, Manson JE, Figueiredo JC, LeBlanc ES, Barrington W, et al. Intentional weight loss and obesity-related
cancer risk. JNCI Cancer Spectr 2019;3(4):pkz054.
[31] Derbyshire AE, MacKintosh ML, Pritchard CM, Pontula A, Ammori BJ, Syed AA, et al. Women's risk perceptions and
willingness to engage in risk-reducing interventions for the prevention of obesity-related endometrial cancer. Int J
Womens Health 2022;14:57e66.
[32] Ryan DH, Johnson WD, Myers VH, Prather TL, McGlone MM, Rood J, et al. Nonsurgical weight loss for extreme obesity in
primary care settings: results of the Louisiana Obese Subjects Study. Arch Intern Med 2010;170(2):146e54.
[33] Mackintosh ML, Crosbie EJ. Prevention strategies in endometrial carcinoma. Curr Oncol Rep 2018;20(12).
[34] Ward KK, Roncancio AM, Shah NR, Davis M-A, Saenz CC, McHale MT, et al. Bariatric surgery decreases the risk of uterine
malignancy. Gynecol Oncol 2014;133(1):63e6.
[35] Anveden Å, Taube M, Peltonen M, Jacobson P, Andersson-Assarsson JC, Sjo €holm K, et al. Long-term incidence of female-
specific cancer after bariatric surgery or usual care in the Swedish Obese Subjects Study. Gynecol Oncol 2017;145(2):224e9.
[36] Mackintosh ML, Derbyshire AE, McVey RJ, Bolton J, Nickkho-Amiry M, Higgins CL, et al. The impact of obesity and
bariatric surgery on circulating and tissue biomarkers of endometrial cancer risk. Int J Cancer 2019;144(3):641e50.
[37] Naqvi A, MacKintosh ML, Derbyshire AE, Tsakiroglou A-M, Walker TDJ, McVey RJ, et al. The impact of obesity and bariatric
surgery on the immune microenvironment of the endometrium. Int J Obes 2022;46(3):605e12.
[38] Endometrial cancer and oral contraceptives: an individual participant meta-analysis of 27 276 women with endometrial
cancer from 36 epidemiological studies. Lancet Oncol 2015;16(9):1061e70.
[39] Faculty of Sexual and Reproductive Healthcare (FSRH) of the Royal College of Obstetricians and Gynaecologists. UK
medical eligibility criteria for contraceptive use 2016. London: FSRH; 2016.
[40] Jareid M, Thalabard J-C, Aarflot M, Bøvelstad HM, Lund E, Braaten T. Levonorgestrel-releasing intrauterine system use is
associated with a decreased risk of ovarian and endometrial cancer, without increased risk of breast cancer. Results from
the NOWAC Study. Gynecol Oncol 2018;149(1):127e32.

14
H.J. Agnew, S.J. Kitson and E.J. Crosbie Best Practice & Research Clinical Obstetrics and Gynaecology 88 (2023) 102337

[41] Derbyshire AE, Allen JL, Gittins M, Lakhiani B, Bolton J, Shaw J, et al. PROgesterone therapy for endometrial cancer
prevention in obese women (PROTEC) trial: a feasibility study. Cancer Prev Res 2021;14(2):263e74.
[42] Clarke MA, Long BJ, Del Mar Morillo A, Arbyn M, Bakkum-Gamez JN, Wentzensen N. Association of endometrial cancer
risk with postmenopausal bleeding in women. JAMA Intern Med 2018;178(9):1210.
[43] Royal College of Obstetricians and Gynaecologists. Malignant disease of the uterus. 2021 [updated June 2021, https://
elearning.rcog.org.uk/malignant-disease-uterus/malignant-disease-uterus.
[44] Morrison J, Balega J, Buckley L, Clamp A, Crosbie E, Drew Y, et al. British Gynaecological Cancer Society (BGCS) uterine
cancer guidelines: recommendations for practice. Eur J Obstet Gynecol Reprod Biol 2022;270:50e89.
[45] National Institute for Health and Care Excellence (NICE). NICE guideline [NG12] Suspected cancer: recognition and
referral [updated 29 January 2021. Available from: https://www.nice.org.uk/guidance/ng12/chapter/1-
Recommendations-organised-by-site-of-cancer#gynaecological-cancers; 2015.
[46] Wise MR, Gill P, Lensen S, Thompson JMD, Farquhar CM. Body mass index trumps age in decision for endometrial biopsy:
cohort study of symptomatic premenopausal women. Am J Obstet Gynecol 2016;215(5):598. e1-.e8.
[47] Gredmark T, Kvint S, Havel G, Mattsson L-A. Histopathological findings in women with postmenopausal bleeding. BJOG
An Int J Obstet Gynaecol 1995;102(2):133e6.
[48] Amy NK, Aalborg A, Lyons P, Keranen L. Barriers to routine gynecological cancer screening for White and African-
American obese women. Int J Obes 2006;30:147.
[49] Ferrante JM, Fyffe DC, Vega ML, Piasecki AK, Ohman-Strickland PA, Crabtree BF. Family physicians' barriers to cancer
screening in extremely obese patients. Obesity 2010;18(6):1153e9.
[50] Timmermans A, Opmeer BC, Khan KS, Bachmann LM, Epstein E, Clark TJ, et al. Endometrial thickness measurement for
detecting endometrial cancer in women with postmenopausal bleeding: a systematic review and meta-analysis. Obstet
Gynecol 2010;116(1):160e7.
[51] Kinkel K, Kaji Y, Yu KK, Segal MR, Lu Y, Powell CB, et al. Radiologic staging in patients with endometrial cancer: a meta-
analysis. Radiology 1999;212(3):711e8.
[52] Connor J, Andrews J, Anderson B, RE B. Computed tomography in endometrial carcinoma. Obstet Gynecol 2000;95(5):
692e6.
[53] Gach HM, Mackey SL, Hausman SE, Jackson DR, Benzinger TL, Henke L, et al. MRI safety risks in the obese: the case of the
disposable lighter stored in the pannus. Radiol Case Rep 2019;14(5):634e8.
[54] Carron M, Safaee Fakhr B, Ieppariello G, Foletto M. Perioperative care of the obese patient. Br J Surg 2020;107(2):e39e55.
[55] Uccella S, Bonzini M, Palomba S, Fanfani F, Ceccaroni M, Seracchioli R, et al. Impact of obesity on surgical treatment for
endometrial cancer: a multicenter study comparing laparoscopy vs open surgery, with propensity-matched analysis.
J Minim Invasive Gynecol 2016;23(1):53e61.
[56] Galaal K, Donkers H, Bryant A, Lopes AD. Laparoscopy versus laparotomy for the management of early stage endometrial
cancer. Cochrane Database Syst Rev 2018;2018(10).
[57] Bouwman F, Smits A, Lopes A, Das N, Pollard A, Massuger L, et al. The impact of BMI on surgical complications and
outcomes in endometrial cancer surgerydan institutional study and systematic review of the literature. Gynecol Oncol
2015;139(2):369e76.
[58] Walker JL, Piedmonte MR, Spirtos NM, Eisenkop SM, Schlaerth JB, Mannel RS, et al. Laparoscopy compared with lapa-
rotomy for comprehensive surgical staging of uterine cancer: gynecologic Oncology Group Study LAP2. J Clin Oncol 2009;
27(32):5331e6.
[59] Corrado G, Vizza E, Cela V, Mereu L, Bogliolo S, Legge F, et al. Laparoscopic versus robotic hysterectomy in obese
and extremely obese patients with endometrial cancer: a multi-institutional analysis. Eur J Surg Oncol 2018;44(12):
1935e41.
[60] Fornalik H, Zore T, Fornalik N, Foster T, Katschke A, Wright G. Can teamwork and high-volume experience overcome
challenges of lymphadenectomy in morbidly obese patients (body mass index of 40 kg/m2 or greater) with endometrial
cancer?: a cohort study of robotics and laparotomy and review of literature. Int J Gynecol Cancer 2018;28(5):959e66.
[61] Podzielinski I, Randall ME, Breheny PJ, Escobar PF, Cohn DE, Quick AM, et al. Primary radiation therapy for medically
inoperable patients with clinical stage I and II endometrial carcinoma. Gynecol Oncol 2012;124(1):36e41.
[62] van der Steen-Banasik E, Christiaens M, Shash E, Coens C, Casado A, Herrera FG, et al. Systemic review: radiation therapy
alone in medical non-operable endometrial carcinoma. Eur J Cancer 2016;65:172e81.
[63] Moszyn
ska-Zielin

ska M, Chałubin _

ska-Fendler J, Gottwald L, Zytko L, Bigos E, Fijuth J. Does obesity hinder radiotherapy in
endometrial cancer patients? The implementation of new techniques in adjuvant radiotherapy - focus on obese patients.
Prz Menopauzalny 2014;13(2):96e100.
[64] Lin LL, Hertan L, Rengan R, Teo BK. Effect of body mass index on magnitude of setup errors in patients treated with
adjuvant radiotherapy for endometrial cancer with daily image guidance. Int J Radiat Oncol Biol Phys 2012;83(2):670e5.
[65] Barr CE, Ryan NAJ, Derbyshire AE, Wan YL, MacKintosh ML, McVey RJ, et al. Weight loss during intrauterine progestin
treatment for obesity-associated atypical hyperplasia and early-stage cancer of the endometrium. Cancer Prev Res 2021;
14(11):1041e50.
[66] Janda M, Robledo KP, Gebski V, Armes JE, Alizart M, Cummings M, et al. Complete pathological response following le-
vonorgestrel intrauterine device in clinically stage 1 endometrial adenocarcinoma: results of a randomized clinical trial.
Gynecol Oncol 2021;161(1):143e51.
[67] Zhang S, Gong T-T, Liu F-H, Jiang Y-T, Sun H, Ma X-X, et al. Global, regional, and national burden of endometrial cancer,
1990-2017: results from the global burden of disease study, 2017. Front Oncol 2019;9:1440.
[68] Secord AA, Hasselblad V, Von Gruenigen VE, Gehrig PA, Modesitt SC, Bae-Jump V, et al. Body mass index and mortality in
endometrial cancer: a systematic review and meta-analysis. Gynecol Oncol 2016;140(1):184e90.
[69] Chia VM, Newcomb PA, Trentham-Dietz A, Hampton JM. Obesity, diabetes, and other factors in relation to survival after
endometrial cancer diagnosis. Int J Gynecol Cancer 2007;17(2):441e6.
[70] Arem H, Park Y, Pelser C, Ballard-Barbash R, Irwin ML, Hollenbeck A, et al. Prediagnosis body mass index, physical activity,
and mortality in endometrial cancer patients. JNCI: J Natl Cancer Inst 2013;105(5):342e9.

15
H.J. Agnew, S.J. Kitson and E.J. Crosbie Best Practice & Research Clinical Obstetrics and Gynaecology 88 (2023) 102337

[71] Donkers H, Fasmer KE, McGrane J, Pijnenborg JMA, Bekkers R, Haldorsen IS, et al. Obesity and visceral fat: survival impact
in high-grade endometrial cancer. Eur J Obstet Gynecol Reprod Biol 2021;256:425e32.
[72] Muratori L, Sperone P, Gorzegno G, La Salvia A, Scagliotti GV. Systemic recurrence of endometrial cancer more than 10
years after hysterectomy: a report of two cases and a brief review of the literature. J Egypt Natl Cancer Inst 2020;32(1).
[73] Jeppesen MM, Jensen PT, Gilså Hansen D, Iachina M, Mogensen O. The nature of early-stage endometrial cancer
recurrenceda national cohort study. Eur J Cancer 2016;69:51e60.
[74] Felix AS, Bower JK, Pfeiffer RM, Raman SV, Cohn DE, Sherman ME. High cardiovascular disease mortality after endo-
metrial cancer diagnosis: results from the surveillance, Epidemiology, and End results (SEER) database. Int J Cancer 2017;
140(3):555e64.
[75] Ward KK, Shah NR, Saenz CC, McHale MT, Alvarez EA, Plaxe SC. Cardiovascular disease is the leading cause of death
among endometrial cancer patients. Gynecol Oncol 2012;126(2):176e9.
[76] Kitson SJ, Lindsay J, Sivalingam VN, Lunt M, Ryan NAJ, Edmondson RJ, et al. The unrecognized burden of cardiovascular
risk factors in women newly diagnosed with endometrial cancer: a prospective case control study. Gynecol Oncol 2018;
148(1):154e60.
[77] Hubert HB, Feinleib M, McNamara PM, Castelli WP. Obesity as an independent risk factor for cardiovascular disease: a 26-
year follow-up of participants in the Framingham Heart Study. Circulation 1983;67(5):968e77.
[78] Rosito G, D'Agostino R, Massaro J, Lipinska I, Mittleman M, Sutherland P, et al. Association between obesity and a pro-
thrombotic state: the framingham offspring study. Thromb Haemostasis 2004;91(4):683e9.
[79] Bogers RP. Association of overweight with increased risk of coronary heart disease partly independent of blood pressure
and cholesterol Levels<subtitle>A meta-analysis of 21 cohort studies including more than 300 000 persons</sub-
title&gt. Arch Intern Med 2007;167(16):1720.
[80] Agnew H, Kitson S, Crosbie EJ. Interventions for weight reduction in obesity to improve survival in women with
endometrial cancer. Cochrane Database Syst Rev 2023;3:CD012513.
[81] Foong KW, Bolton H. Obesity and ovarian cancer risk: a systematic review. Post Reprod Health 2017;23(4):183e98.
[82] Olsen CM, Nagle CM, Whiteman DC, Ness R, Pearce CL, Pike MC, et al. Obesity and risk of ovarian cancer subtypes:
evidence from the Ovarian Cancer Association Consortium. Endocr Relat Cancer 2013;20(2):251e62.
[83] Collaborative Group on Epidemiological Studies of Ovarian C. Ovarian cancer and body size: individual participant meta-
analysis including 25,157 women with ovarian cancer from 47 epidemiological studies. PLoS Med 2012;9(4):e1001200.
[84] Dixon SC, Nagle CM, Thrift AP, Pharoah PD, Pearce CL, Zheng W, et al. Adult body mass index and risk of ovarian cancer by
subtype: a Mendelian randomization study. Int J Epidemiol 2016;45(3):884e95.
[85] World Cancer Research Fund/American Institute for Cancer Research. Continuous update project expert report. In: Diet,
nutrition, physical activity and ovarian cancer.2018; 2018 [cited 2022 16th November]. Available from,
dietandcancerreport.org.
[86] Baumeister SE, Schlecht I, Trabert B, Nolde M, Meisinger C, Leitzmann MF. Anthropometric risk factors for ovarian cancer
in the NIH-AARP Diet and Health Study. Cancer Causes Control 2021;32(3):231e9.
[87] Huang T, Tworoger SS, Willett WC, Stampfer MJ, Rosner BA. Associations of early life and adulthood adiposity with risk of
epithelial ovarian cancer. Ann Oncol 2019;30(2):303e9.
[88] Office for National Statistics. Health Survey for England 2019 [cited 2022 9th November]. Available from: https://digital.
nhs.uk/data-and-information/publications/statistical/health-survey-for-england/2019#top; 2019.
[89] Smits A, Lopes A, Das N, Kumar A, Cliby W, Smits E, et al. Surgical morbidity and clinical outcomes in ovarian cancer - the
role of obesity. BJOG 2016;123(2):300e8.
[90] Bandera EV, Lee VS, Rodriguez-Rodriguez L, Powell CB, Kushi LH. Impact of chemotherapy dosing on ovarian cancer
survival according to body mass index. JAMA Oncol 2015;1(6):737e45.
[91] Lyman GH, Sparreboom A. Chemotherapy dosing in overweight and obese patients with cancer. Nat Rev Clin Oncol 2013;
10(8):451e9.
[92] Bae HS, Kim HJ, Hong JH, Lee JK, Lee NW, Song JY. Obesity and epithelial ovarian cancer survival: a systematic review and
meta-analysis. J Ovarian Res 2014;7:41.
[93] Cancer Research UK. Cervical Cancer Risk [cited 2022 December 22nd]. Available from: https://www.cancerresearchuk.
org/health-professional/cancer-statistics/statistics-by-cancer-type/cervical-cancer/risk-factors#heading-Seven.
[94] Lacey Jr JV, Swanson CA, Brinton LA, Altekruse SF, Barnes WA, Gravitt PE, et al. Obesity as a potential risk factor for
adenocarcinomas and squamous cell carcinomas of the uterine cervix. Cancer 2003;98(4):814e21.
[95] Ursin G, Pike MC, Preston-Martin S, d'Ablaing 3rd G, Peters RK. Sexual, reproductive, and other risk factors for adeno-
carcinoma of the cervix: results from a population-based case-control study (California, United States). Cancer Causes
Control 1996;7(3):391e401.
[96] Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ. Overweight, obesity, and mortality from cancer in a prospectively
studied cohort of U.S. Adults. N Engl J Med 2003;348(17):1625e38.
[97] Maruthur NM, Bolen SD, Brancati FL, Clark JM. The association of obesity and cervical cancer screening: a systematic
review and meta-analysis. Obesity 2009;17(2):375e81.
[98] Kizer NT, Thaker PH, Gao F, Zighelboim I, Powell MA, Rader JS, et al. The effects of body mass index on complications and
survival outcomes in patients with cervical carcinoma undergoing curative chemoradiation therapy. Cancer 2011;117(5):
948e56.
[99] Cancer Research UK. Vulval cancer statistics [cited 2022 December 22nd]. Available from: https://www.
cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/vulval-cancer#heading-Zero.
[100] Cancer Research UK. Vaginal cancer statistics [cited 2022 December 22nd]. Available from: https://www.
cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/vaginal-cancer#heading-Zero.
[101] Bucchi L, Pizzato M, Rosso S, Ferretti S. New insights into the Epidemiology of vulvar cancer: systematic literature review
for an update of incidence and risk factors. Cancers [Internet] 2022;14(2).
[102] Klapdor R, Hillemanns P, Wo €lber L, Jückstock J, Hilpert F, de Gregorio N, et al. Association between obesity and vulvar
cancer recurrence: an analysis of the AGO-CaRE-1 study. Int J Gynecol Cancer 2020;30(7):920e6.

16