Download Endometrial Cancer in Obese Women

Endometrial Cancer in
Obese Women
Scientific Impact Paper No. 32
May 2012
Endometrial Cancer in Obese Women
1.
Introduction
Obesity is now affecting 25% of adults in the UK1 and predisposes women to endometrial as well as
other cancers. In 2007, the UK government-commissioned Foresight report predicted that if no action
were taken, 60% of men, 50% of women and 25% of children would be obese by 2050. Excess body
weight is known to be associated with an increased risk of many malignancies and the risk of
endometrial cancer is strongly associated with obesity.2,3 Obesity is predominantly associated with
type 1 (endometroid) endometrial cancers4 rather than type 2 (non-endometroid type such as serous or
carcinosarcoma) endometrial cancer; however, both sub-types are increased with obesity.5 Risk of
endometrial cancer is increased in women with a body mass index (BMI) greater than 30 kg/m26 and the
risk increases linearly with increasing BMI.5,7 In the UK, approximately 50% of endometrial cancers are
attributable to obesity.8
Endometrial cancer is the fourth most common cancer in women in the UK with 7536 cases diagnosed
in 2007, accounting for around 5% of all female cancers.9–11 The incidence of endometrial cancer is rising
in postmenopausal women, but 5-year survival rates have improved to more than 77%, although women
from deprived backgrounds have up to a 4% lower 5-year survival.12 In the UK, the incidence of uterine
cancer remained stable between 1975 and 1993, but increased by more than 40% between 1993 and
2007. The incidence rates peak between the ages of 60 and 79, the age range within which
the largest increases have occurred, with rates doubling since 1975, rising from 40 to over 75 in every
100 000 women in 2007.
Standard treatment for endometrial cancer is surgery (historically total abdominal hysterectomy and
bilateral salpingo-oophorectomy, removal of uterus, cervix, tubes and ovaries, with or without lymph
node dissection) with adjuvant treatment in the form of radiotherapy and/or chemotherapy as indicated.
Preoperative assessment of endometrial cancer may be problematic in obese women. A magnetic
resonance imaging (MRI) scan is often used for assessment of endometrial cancer, but many scanners
have a weight limit which prohibits scanning morbidly obese patients.
A BMI >30 kg/m2 indicates obesity and is associated with an increased risk of perioperative
complications, while a BMI >40 kg/m2 is described as morbid obesity and is associated with higher rates
of complications.13 Obesity is associated with numerous disorders, notably diabetes, hypertension and
cardiovascular disease. In morbidly obese women, perioperative complications such as obstructive sleep
apnoea, arrhythmias, acute cardiac events and venous thrombotic events are more common. Obese and
morbidly obese women are therefore likely to require more detailed preoperative assessment to reduce
the sequelae of co-existing morbidity and more intensive postoperative care. The challenges of
perioperative care for such patients are likely to impact on medical, nursing and psychosocial resources.
Thus, treatment for endometrial cancer needs to be reassessed in the complex and increasingly common
situation of the obese older woman with this disease.
2.
Surgery
Laparoscopic hysterectomy and bilateral salpingo-oophorectomy has been demonstrated to be the
surgical technique of choice for women with endometrial cancer in three large randomised controlled
trials.14–16 In an American randomised controlled trial, the Gynecologic Oncology Group (GOG) LAP2
study, all women underwent pelvic and para-aortic lymphadenectomy at the time of hysterectomy and
bilateral salpingo-oophorectomy,14 while in an Australian, New Zealand and Hong Kong randomised
controlled trial women could be excluded for lymph node staging if they were obese, had early-stage
disease or were medically unfit (52% had lymphadenectomy).15 In a Dutch randomised controlled trial,
women had only hysterectomy and bilateral salpingo-oophorectomy.16
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Laparoscopic hysterectomy has the benefits of shorter hospitalisation,14–16 reduced analgesic
requirements,15 superior quality of life scores15,17,18 and resumption of daily activities.16,18 Laparoscopic
surgery by experienced surgeons did not result in any more significant intraoperative complications than
open surgery.16 All patient-reported outcome measures were significantly better after laparoscopic
surgery in women with BMIs less than 35 kg/m2. In both the GOG14 and the Dutch study,16 women with
high BMIs had a higher conversion rate from laparoscopic to open surgery. In the GOG trial,14 there were
significantly more postoperative events after abdominal hysterectomy, but this was not the case in the
other two randomised controlled trials. In the GOG study, 26.5% of women with a BMI of
34–35 kg/m2 were converted to open procedures and 57.1% of women with a BMI greater than 40
kg/m2 were also converted to open surgery.14 In the Dutch study, a BMI over 35 kg/m2 was associated
with a conversion rate of 32.3%.16 These trials reported conversion rates in thin patients of 17.5% and
6.5% respectively, perhaps reflecting the inclusion of pelvic and para-aortic lymphadenectomy in the
American study14 and not in the Dutch study.16 In the Australian study,15 the conversion rate was low for
all procedures at 3.6% and not reported in relation to BMI.
In a case series from the Hammersmith hospital with highly trained laparoscopic surgeons, the
conversion rate to open surgery in 191 women undergoing laparoscopic hysterectomy and salpingooophorectomy for endometrial cancer which included 60% patients with a BMI ≥ 30 was 1.04%.20
Bijen et al. performed a randomised controlled trial on the outcomes from laparoscopic hysterectomy for
endometrial cancer. The conversion rate for women over 70 years of age was the same as for younger
women (10.5%); however, there was a significant difference in women with a BMI >35 kg/m2.19 The
estimated risk of conversion from laparoscopy to laparotomy increases with BMI, with a steep rise in
women with a BMI >35 kg/m2. The major complication rate in women with BMI >35 kg/m2 undergoing
laparoscopic surgery was similar to open surgery (25%). The authors concluded that it was not costeffective to perform laparoscopic hysterectomy in high-BMI women.19 However, it is of note that the
conversion rate in this study was much higher than in the other studies mentioned, which would account
for the lack of cost-effectiveness.
Laparoscopic hysterectomy has been demonstrated to improve patient-reported outcomes compared
with open surgery in the short term but there is no significance difference other than body image at
6 months.18 In a randomised controlled trial of the use of laparoscopic hysterectomy for treatment of
endometrial cancer, both in the early phase of recovery and 6 months postoperatively, patients who had
laparoscopic hysterectomy reported significantly greater improvement in quality of life measures from
baseline compared with those who had an open hysterectomy, in all subscales apart from emotional and
social wellbeing.15
Many authorities recommend modified apronectomies to improve surgical access and reduce long-term
wound morbidity in morbidly obese women.21,22 These retrospective case series report significantly lower
wound complication rates compared with mid-line laparotomy alone. Apronectomy was associated with
a four-fold reduction in wound morbidity compared with standard laparotomy approach. Surgical time
for hysterectomy combined with apronectomy in women who are obese is significantly prolonged
compared with hysterectomy alone, with an American case series23 reporting the following surgical times:
median 265 minutes (range 171–355) compared with 168 minutes (range 40–368), i.e. an average
additional operating time of more than one and a half hours. However, Umeadi reported a UK case series
of apronectomies at the time of hysterectomy; in this series, surgery time was median 167 minutes (range
120–522), which is equivalent to the hysterectomy-only group in the American case series.22,23
Hysterectomy combined with apronectomy has been shown to result in prolonged hospitalisation.21,23,24
Vaginal hysterectomy and bilateral salpingo-oophorectomy performed under regional anaesthesia may
be an alternative route for surgery in obese women not fit for general anaesthetic. However, this route
does not allow direct visualisation of the peritoneal surfaces and can be challenging in very obese
postmenopausal women. Surgical times are significantly prolonged in obese patients.25 In addition,
abdominal hysterectomy in obese women is known to have a high morbidity, with a significant increase
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in wound infection, wound separation and re-hospitalisation compared with surgery in the non-obese.26–28
This is not surprising as a recent report suggests that tissue antibiotic levels may be sub-therapeutic in
obese women when given in standard doses.29 One of the advantages of laparoscopic hysterectomy in
obese women is the low rate of wound infection compared with laparotomy.30 Obesity-related wound
complications after colectomy were estimated to be 60% more frequent compared with non-obese cases,
and were estimated to increase hospital costs by US$17,324 per case in the US in 2011.31 Similarly, the
increased estimated costs of obesity-related wound infections in cholecystectomy and appendicectomy
were estimated to be US$1,109 and US$666 in another recent study by the same group.32 To date there
are no published reports on the economic impact on health services of hysterectomy in relation to obesity
either in the US or UK.
One of the major controversies in the management of endometrial cancer is the role of lymph node
dissection (pelvic and possibly para-aortic) at the time of surgery. Lymph node dissection may be used
for accurate staging of endometrial cancer or may have a therapeutic role. The therapeutic role of
lymphadenectomy is still not proven in prospective trials; however, some retrospective reports suggest a
therapeutic benefit for patients with high-risk early-stage endometrial cancer.33 In morbidly obese
women, the addition of lymphadenectomy may result in more complications owing to difficulties with
surgery in this group of women, and possibly higher conversion rates for laparoscopic procedures. In
a retrospective case series, the median duration of hysterectomy without lymphadenectomy in women
with a BMI >35 kg/m2 was 145 minutes (range 40–335) at laparotomy and 203 (range 94–330) at
laparoscopy.21 Median laparoscopic operating times in women with a high BMI were significantly longer
(95 minutes) than low-BMI women (60 minutes).20 In the LAP2 randomised controlled trial that
included lymphadenectomy on all patients, a high BMI was also associated with prolonged surgery and
higher conversion rates to open surgery.14 In the Australasian randomised controlled trial,
lymphadenectomy was optional in high-BMI women.15
3.
Primary radiotherapy
Endometrial cancer is radiosensitive and radiotherapy may be used as a sole treatment modality.
Although there have been no direct comparisons of primary radiotherapy with surgery in women with
local disease and significant comorbidities, early case series suggest that primary radiotherapy has
inferior survival rates compared with hysterectomy, with the risk of intrauterine recurrence.
Radiotherapy as primary treatment of endometrial cancer is only considered in exceptional cases;
recurrence rates of up to 18% have been reported in these patients in a recent retrospective study.34
Radiotherapy is administered either as a combination of external beam radiotherapy and brachytherapy
or as brachytherapy alone.34 The justification for using external beam radiotherapy is that some patients
have occult pelvic sidewall disease, particularly with high-grade tumours, and its inclusion might
improve outcomes. The inclusion of external beam radiotherapy might be considered over-treatment in
early-stage low-grade disease. However, reports suggest a 5–20% rate of late radiation toxicity when
combining external beam and intracavitary radiotherapy.35
External beam radiotherapy of the pelvis in obese patients is also complicated by anatomical changes in
these patients owing to the amount of adipose tissue. The target organ may shift, resulting in a reduced
dose being delivered to it. Higher failures with radiotherapy to pelvic cancers have been reported in
prostate cancer.36 Image-guided planning and treatment may overcome some of these problems.
The majority of early publications report on low-dose-rate (LDR) brachytherapy with later studies
reporting on high-dose-rate (HDR) brachytherapy. HDR offers the benefit of shorter treatment times.
These case series tend to include women who are unfit for surgery owing to medical comorbidities –
including significant obesity – and the majority of published case series were conducted prior to
computerised radio-planning. In these case reports, death rates owing to intercurrent disease were high,
but reported disease-specific 5-year survival rates35 were similar to surgical cure rates.
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4.
Progestogens
Many clinicians faced with the dilemma of low-grade endometrial cancer in women with morbid obesity
and comorbidity are prepared to use progestogens, particularly administered by intrauterine system
(IUS), as a conservative management of disease. However, there are no large case series reporting on the
outcome of such medical management as a primary treatment and the long-term outcome of such
management is unclear. There are several small case series of using either the oral route or IUS to
administer progestogens in young women with severe endometrial atypia or low-grade endometrial
cancer who wish to preserve their fertility.37 The results of these studies are heterogeneous and may not
necessarily apply to obese patients with endometrial cancer.
Studies in a recurrence setting (irrespective of the patient’s weight) with high-dose oral progestogens
report an objective response rate from 11% to 25%.38,39 Most responses are partial and of relatively short
duration, although some patients remain free of disease progression for more than 12 months.40
5.
Cancer prevention and survivorship
The association between obesity, the resultant metabolic changes and endometrial cancer is well
established. The rationale for prevention of endometrial cancer is based on our understanding of the
cellular and molecular pathways involved in this cancer. Use of the combined contraceptive pill is
associated with reduction in risk of developing endometrial cancer; however, the pill may not be safe for
use in obese women (UKMEC).41 Use of the Mirena IUS, weight loss, exercise and use of oral
hypoglycaemic drugs (e.g. metformin) for control of diabetes have all been suggested as a means of
prevention of endometrial cancer in obese women.42 Bariatric surgery that results in sustained weight loss
has also been linked with reduction in risk of developing cancer, more noticeably in women.43
The Cancer Reform Strategy (2007) outlined the need for a National Cancer Survivorship Initiative
to improve the care and support provided for those living with and beyond cancer. Women with
endometrial cancer will require generic physical/psychological support after initial treatment in keeping
with the survivorship agenda. Women who are significantly overweight are likely to benefit from tailored
lifestyle interventions to enhance general wellbeing and to reduce the risk of recurrence.
Obesity is associated with non-cancer-related comorbidities such as diabetes, cardiovascular disease,
hypertension and pulmonary disease that might also have a negative impact on morbidity and survival.
In two US surveys of endometrial cancer survivors, obesity was associated with a low level of physical
activity, poor physical functioning, fatigue and pain.44,45 Obese endometrial cancer survivors often have
comorbidities restricting their lifestyle, and this has a negative impact on quality of life measures.
The growing evidence base suggests that obesity has a negative impact not only on cancer-related
outcomes but also on women’s global wellbeing. Weight management should be advocated as an
important component of the NHS survivorship agenda.46 Despite the adverse effects of obesity in cancer
survivors, only five studies47–51 have assessed weight management in cancer populations. Two of these
studies48,51 looked mainly at survivors who had completed active treatment, and reported that individual
dietary counselling provided by a dietician was effective in promoting weight loss. Three studies have
shown that physical exercise reduces the risk of cancer recurrence and overall survival in breast and
colon cancer.46 A study in breast and prostate cancer survivors suggested that the optimum time to
influence lifestyle changes was shortly after diagnosis52 and that lifestyle interventions are more likely
to be sustained in women.53 In a small randomised controlled trial of 45 obese women surviving
endometrial cancer, a counselling programme including a psychologist and dietician improved eating
behaviour and emotional wellbeing but not quality of life.54
In July 2011, the UK government set out a framework for delivery of public health, entitled ‘Healthy
lives, healthy people. White Paper: Update and way forward’, in which prevention of obesity and lifestyle
initiatives become the responsibility of public health through local authorities.55 Lifestyle changes were
to be encouraged within this framework, and the Department of Health published physical activity
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guidelines including specific recommendations for the elderly and obese.56 These themes were endorsed
in the RCOG’s Expert Advisory Group report in July 2011, ‘High Quality Women’s Health Care: A
proposal for change’, which promotes a life-course approach, in tandem with primary care strategies to
promote better health by reducing obesity. The multidisciplinary gynaecological oncology team needs to
exploit the opportunity of lifestyle changes in women undergoing treatment and subsequent follow-up
within the new survivorship agenda.57
6.
Opinion
Surgery for endometrial cancer in obese patients presents challenges to surgeons, anaesthetists and nursing
teams. Laparoscopic surgery is the optimum approach in order to minimise postoperative wound
complications and encourage early discharge from hospital. Surgery, whether laparoscopic or open, is
challenging and is very much dependent on the expertise of the operator. High conversion rates in
morbidly obese patients in some randomised controlled trials of laparoscopic hysterectomy illustrate that
the choice of surgical route has to be carefully considered depending on available local expertise.
Abdominoplasty at open procedures is time consuming but reduces perioperative morbidity, and the
morbidity of such procedures is likely to be reduced by an experienced surgeon. Ideally, all gynaecological
cancer centres should offer expertise in surgery for morbidly obese women to their networks, as individual
units are unlikely to develop such experience. Centres should encourage training in operative techniques
that enhance skills in laparoscopic surgery and abdominoplasty. There are no data currently available to
evaluate the clinical or cost effectiveness of robotic surgery in the management of these women.
Laparoscopic or open surgery in morbidly obese women exerts demands on the local health economy:
preoperative investigations can be extensive, the duration of surgery can be prolonged, patients often
require high-dependency postoperative care, surgical wards need specific equipment for such patients,
and hospitalisation can be prolonged. At present, there is no enhanced tariff for hysterectomy in
morbidly obese women compared with women of low BMI. Centralisation of surgery of morbidly obese
women with endometrial cancer is likely to reduce morbidity, but delivering such a quality service needs
to be recognised by an uplift in tariff/revenue for such complex cases. Thought should also be given to
investment in training of surgeons in appropriate technologies such as laparoscopic surgery to deal with
the increasing number of morbidly obese patients.
Primary radiotherapy may be a viable treatment modality in patients with significant comorbidities and
a prospective nationwide registry of such cases should be considered. Finally, the gynaecological
oncology community needs to develop a definitive study of progestogens, administered either orally or
by IUS, for the primary treatment of low-grade endometrial cancers in obese women with comorbidities
precluding surgery before their use in this setting becomes commonplace.
Specific patient-centred information is needed for obese women undergoing management for
endometrial cancer. Furthermore, the optimum timing and nature of interventions to promote better
lifestyles needs to be ascertained in clinical trials, as there is limited evidence for such strategies,
particularly in gynaecological oncology.
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© Royal College of Obstetricians and Gynaecologists
This Scientific Impact Paper was produced on behalf of the Royal College of Obstetricians and Gynaecologists by:
Dr PL Martin-Hirsch FRCOG, Lancashire and Dr S Ghaem-Maghami MRCOG, London
and peer reviewed by: BGCS; BSGE; RCOG Consumers’ Forum; Mr RAF Crawford FRCOG, Cambridge; Professor HC Kitchener
FRCOG, Manchester; Mr TAJ Mould FRCOG, London; Mr CWE Redman FRCOG, North Staffordshire.
The Scientific Advisory Committee lead reviewer was: Dr DG Tincello FRCOG, Leicester.
The final version is the responsibility of the Scientific Advisory Committee of the RCOG.
The review process will commence in 2015, unless otherwise indicated.
Scientific Impact Paper No. 32
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© Royal College of Obstetricians and Gynaecologists