Obesity & Endometrial cancer

Wafaa B. BastaSpecialist Gynaecology & Obstetrics at Mataria Teaching Hospital

MBBch., MSc., Egyptian Fellowship, MRCOGERC MEMBER

One of the most serious public health problems of the 21st century.

Obesity is a leading preventable cause of death worldwide.

Is Obesity a problem?

Genetics

Behavior

Environment

Causes of Obesity

Body mass index ( BMI)

a person’s weight in kilograms square of height in metres (kg/m2).

  * <18.5 : Underweight * 18.5-24.9 : Normal/Healthy * 25.0-29.9 : Overweight (pre-obese) * 30.0-34.9 : Obese (Class I) * 35.0-39.9 : Obese (Class II) * ≥40  Obese ( Class III = morbid obesity)

o Waist –hip ratio correlates more with the metabolic disorder.

BMI classification (WHO & NICE)

Obesity. Guidance on the prevention, identification, assessment and management of overweight and obesity in adults and children. London: (NICE), 2006.

In1997 : obesity is a global epidemic.

At 2008 : 1.5 billion individuals < 20 ys. are obese.

Obesity rates are rising worldwide. Obesity: Preventing and managing the

global epidemic. Geneva : WHO , 2000.

Prevalence of Obesity Worldwide

25% of adults in the UK are now obese .

50% of women would be obese by 2050. ( if no action were taken). [The Government commissioned Foresight report 2007]

Incidence of obesity in UK

Statistics on Obesity, physical activity & diet :England 2010 in NHS information centre for life style statistics 2010.

About one-third of U.S. adults (33.8%) are obese.

Incidence of obesity in USA

National Health & Nutrition Examination Survey (NHANES) 2007 -2008

In 1992, mothers with young children had a mean (BMI) of 26.9.

By 2005, rise to a mean BMI of 30.1, with nearly 50% of Egyptian women of reproductive age classified as obese.

Prevalence of Obesity In Egypt

WHO study (Musaiger 2004) Demographic and Health Surveys

How Often is Endometrial Cancer?

The most common cancer of the female genital tract.

The fourth most common cancer in women. 5% of all female cancers in 2007. (ASR 19.4) 1975 - 1993 : Incidence remained stable. 1993 - 2007 : Incidence increased by <40% .

Incidence of endometrial cancer in Uk

Cancer statistics registrations ; Registrations of cancer diagnosed in 2007 , England 2010, National statistics ,London

Gharbia Population Based Cancer Registry 2002-2003: Endometrial cancer is the 2nd Gynaelogical cancer in female, 9th of all female cancers. (ASR 2.1%)

Incidence of uterine cancer in urban areas is almost 6 times higher than rural ones.

Aswan Population Based Cancer Registry 2008: Endometrial cancer is the 2nd Gynaelogical cancer in female,6th of all female cancers. (ASR 4.1%)

ASR= Age Standardised Incidence Rate

Incidence of endometrial cancer in Egypt

WHO : overweight and obesity are the most important known avoidable cause of cancer after tobacco.

No. 1No.2

WHO/FAO, Joint WHO/FAO Expert Consultation on Diet, Nutrition and the Prevention of Chronic Diseases, in WHO Technical Report Series. 2003, WHO: Geneva

• Major studies confirmed that being overweight or obese increases risk of various cancers.

Esophagus Pancreas Colon and rectum Breast (after menopause) Endometrium Kidney Thyroid Gallbladder

Obesity & cancer

 Renehan, A.G., et al., Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies. Lancet 2008. 371(569-578).

Overweight and obesity are behind around 17,000 cases of cancer each year in the UK.

Obesity Cancer link UK

 Parkin, M., et al., The fraction of cancer attributable to lifestyle and environmental factors in the UK in 2010. BJC 2011. 105, Supp. 2, 6 December 2011

In 2007 : 50,500 cancer in women (7 %) were due to obesity.

By 2030 : obesity will lead to about 500,000 additional cases of cancer in the USA.

Obesity Cancer link USA

NCI Surveillance, Epidemiology, and End Results (SEER) data, 2007 , United States

Risk of endometrial cancer is increased in women with a BMI greater than 30kg/m2

The risk increases linearly with increasing BMI.

In the UK, approximately 50% of endometrial cancers are attributable to obesity.

Obesity & Endometrial cancer

 Reeves, G.K., et al., Cancer incidence & mortality in relation to BMI in the Million Women Study: BMJ 2007

Obese women are 3 to 4 times more likely to develop endometrial cancer than people with a healthy bodyweight ,regardless of menopausal status.

obesity and endometrial cancer

Friedenreich, C., et al., Anthropometric factors and risk of endometrial cancer: the European prospective investigation into cancer and nutrition. Cancer Causes Control, 2007

Obesity is predominantly associated with type1(endometroid) endometrial cancer, rather than type 2 (non-endometroid type such as serous or carcino-sarcoma).

However, both subtypes are increased with obesity.

McCulloiugh, M.L.,et al., body mass & endometrial cancer risk by HRT & cancer subtypes. Cancer Epidemiol Biomarkers Prev,2008

Endometrial Cancer Sub-types

How Obesity leads to Endometrial cancer ?

In pre-menopausal women: obesity ----- anovulatory cycles, the endometrium

is exposed to un-opposed oestrogen. In post-menopausal women:

obesity ----- increased conversion of androstenedione to oestrone in adipose tissue + lower levels of SHBG----- higher levels of unopposed oestrogen.

Possible Mechanisms

Increased levels of insulin and Insulin-like growth factor-1 (IGF-1)

Fat cells produce hormones, called adipokines, that may stimulate or inhibit cell growth. ( e.g. leptin, promote cell proliferation , whereas adiponectin,, may have anti-proliferative effects ).

Other Possible Mechanisms

Fat cells may also have direct and indirect effects on other tumor growth regulators, including mammalian target of rapamycin (mTOR) and AMP-activated protein kinase.

Obese people often have chronic low-level, or “sub-acute,” inflammation, which has been associated with increased cancer risk.

Other possible mechanisms include altered immune responses, effects on the nuclear factor kappa beta system, and oxidative stress.

Other Possible Mechanisms

Apple-shaped people who put on weight around their stomach may have higher risks than pear-shaped people who put on weight around their hips.

Abdominal Fat

Abdominal fat is measured using either waist circumference or waist-to-hip ratio .

Studies have found that people with larger waists or waist-to-hip ratios have higher risks of certain cancers .

Normal waist-to-hip ratio in female 0.7,waist is 30% smaller than hip.

Abdominal Fat

A study was conducted in Alexandria, Egypt.◦ It intended to assess the relation between

different measures of obesity and the risk to develop endometrial cancer in Egyptian females with postmenopausal bleeding (PMB).

◦ Result: Using ROC curve analysis, only the measure of abdominal obesity (waist circumference) showed significant accuracy in predicting endometrial cancer (area = 0.63, P < .05). The best cutoff point that maximizes accuracy was 88 cm.

Abdominal Obesity and Endometrial Cancer in Egyptian Females With PMB

Zaki.A, Gaber.A, Ghanem .E, Moemen.M, Shehata G. Biomedical Informatics and Medical Statistics Department, Medical Research Institute, Alexandria University, Egypt.

Prevention of Endometrial Cancer

Research is focusing on improved evaluation of risk, so that women can receive the optimal chemo-preventive agent when diagnosed as being at high risk of cancer.

Current trends in cancer ttt

Risk Identification

Preventive measures

Screening Program

Obese women. Early Menarche. Late Menopause. Polycystic ovary syndrome. Type 2 Diabetes. Hypertension. An-ovulatory Infertility. HNPCC (hereditary non-polyposis colon cancer) Tamoxifin therapy. HRT.

High Risk Group

Weight loss: Life Style changes(diet & exercise).

Pharmaco-therapy . Bariatric surgeries.

Chemo-prophylaxis :*COCP *Oral progesterone *Injectable progesterone * Mirena IUS

Preventive Measures

Large studies are now trying to confirm that losing weight may reduce cancer risk.

One study : loss of 20 pounds ---11% decrease in overall cancer risk.

Another study: women who had sustained some degree of weight loss for 5 years or more had a 25% lower risk of developing endometrial cancer than those who had not lost weight.(1)

Weight Loss

Trentham-Dietz A, Nichols H, Hampton J, Newcomb P. Weight change and risk of endometrial cancer. Int J Epidemiol 2006

Weight loss

Non-surgical

Behavioral changes Diet

Exercise Pharmacotherapy

Bariatric surgery

Bariatric surgery

Traditional methods of weight loss are less successful than bariatric surgery to induce successful long-term weight loss.!!!!!!!!

A study based on ongoing Swedish Obese Subjects trial :

Bariatric surgery that results in sustained weight loss may help to reduce cancer risk in obese women.

The Lancet Oncology, Swedish study based on ongoing Swedish Obese Subjects trial

Bariatric surgery

COC use for about 3 years reduces a women's risk of developing endometrial cancer by about 50%.

Use of COCs for 10 years or more reduces a woman's risk of developing such cancers by 80%.

The protective effect lasts for up to 20 years after cessation of COCs.

COCs

Hannaford PC, Selvaraj S, Elliott AM, Angus V, Iversen L, Lee AJ. “Cancer risk among users of oral contraceptives: cohort data from the Royal College of Practitioner’s oral contraception study”. BMJ online 12 Sept 2007

However , Obese women using oral contraceptives may also have a higher failure rate as a contraceptive .

Also obesity complications as hypertension , diabetes, cardiovascular disease and thrombo-embolism may limit COCs use.

COCs

Depo-Provera reduces the risk of endometrial cancer by 80%.

The reduced risk of endometrial cancer in Depo-Provera users is thought to be due to both the direct anti-proliferative effect of progestogen on the endometrium and the indirect reduction of estrogen levels by suppression of ovarian follicular development.

WHO Collaborative Study of Neoplasia and Steroid Contraceptives (1991). "Depot-medroxyprogesterone acetate (DMPA) and risk of endometrial cancer". Int J Cancer

DMPA

DMPA ( Depo-Provera) and the combination contraceptive vaginal ring (NuvaRing) are most effective for obese women because they don't appear to be affected by body weight.

DMPA

Progestogen-containing IUCDs (Mirena) might considered partially chemo-preventive although as yet there are no data to support them being prophylactic.

The POET study (Prevention Of Endometrial Tumours), shortly to be launched, will look at a small group of women who are deemed to be genetically predisposed to develop endometrial cancer at a young age and will evaluate progestogen-containing IUCDs in this setting.

MIRENA IUS

Year Total cc.

Pill Injectable +Implants

IUCD FemaleSterliz

Male Sterliz

Condom

UK 2002 84 % 22 % 3 % 6 % 13% 17% 18%

Egypt 2003 60% 9.3 % 8.8% 36.7% 0.9% 0% 0.9%

United Nations .Department of economic & social affairs. Population Division. World contraceptive use.

Contraception prevalence (In women aged 15-45ys who are married or in union)

Screening of Endometrial Cancer

At present, there are not screening methods with acceptable sensitivity and specificity.

Ultrasound imaging: endometrial thickness 4 mm cut value reliable in postmenopausal women experiencing bleeding, but the test carries a high false positive rate in asymptomatic women.

The idea that combination of TVS and color Doppler can reduce the number of false-positive findings, are still under research .

Gupta, J.K., et al., Ultrasonographic endometrial thickness for diagnosing endometrial pathology in women with postmenopausal bleeding: a meta-analysis. Acta Obstet Gynecol Scand, 2002

Screening

Cytological sampling is technically viable, but there is no evidence from RCTs to support its use .

The Cancer Genetics Studies Consortium recommends gynaecological screening for women with HNPCC syndrome, but there is no clear evidence that ultrasound screening in this group is of benefit.

screening

Treatment of Endometrial Cancer

Standard treatment ( Abdominal hysterectomy and bilateral SO , with or without radiotherapy and/or chemotherapy).

Laparoscopic hysterectomy. Primary Radiotherapy.

TTT of Endometrial Cancer

Hysterectomy and bilateral SO , with or without radiotherapy and/or chemotherapy as indicated.

Obesity is associated with an increase risk of peri-operative complications due to associated disorders as diabetes, hypertension, and cardiovascular disease.

In morbidly obese women , obstructive sleep apnoea is 10 times more common and puts post-operative patients at risk of arrhythmia and acute cardiac events.

So, more detailed preoperative assessment to exclude co-existing morbidity and more intensive postoperative care is required.

Standard treatment

Neither the PORTEC trial nor the more recent ASTEC trial has suggested a meaningful role for pelvic lymph-adenectomy, although sampling of the nodes remains a part of FIGO staging.

Standard treatment

Laparoscopic hysterectomy &bilateral SO has been demonstrated to be the surgical technique of choice for women with endometrial cancer in three large RCTs :

1. The American RCT, the Gynecologic Oncology Group (GOG) LAP2 study.

2. The Australian, New Zealand and Hong Kong RCT.3. The Dutch RCT.

However, a higher conversion rate to open surgery was noticed with high BMI.

Laparoscopic hysterectomy

Endometrial cancer is radiosensitive. Radiotherapy may be used as a sole

treatment modality. There have been no direct comparisons of

primary radiotherapy with surgery in women with local disease and significant co morbidities, early case series suggest that primary radiotherapy has inferior survival rates compared to hysterectomy.

Primary Radiotherapy

Inciura, A., et al., Long-term results of high-dose-rate brachytherapy and external-beam radiotherapy in the primary treatment of endometrial cancer. J Radiat Res (Tokyo)

May be used in selected cases for fertility reservation.

Early case series to be used in early stages with obesity co-morbidites.

In atypia & well-differentiated stage (1a ) cancer.

Progestagen

Obesity is now clearly established as a major risk factor for endometrial cancer.

In medium income country like ours , Obesity prevention and lifestyle initiatives should become the responsibility of public health services. Stepwise programmes with realistic time-related goals are required, starting with modification of lifestyle, progressing to pharmacotherapy and ultimately obesity surgery.

The real challenge now is to triage those women at a higher risk and offer them prophylactic measures as COCPs ,DMPA, oral progesterone or Mirena coil.

Conclusion

Standard treatment for endometrial cancer is surgery.

Obesity is associated with numerous disorders which put the patient at increase risk of peri-operative complications that require more detailed pre-operative assessment and more intensive post-operative care.

Thus treatment for endometrial cancer needs to be reassessed in the complex and increasingly common situation of the obese, older women with this disease.

Conclusion

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