Adaptive Medicine 4(1): 15-19, 2012 DOI: 10.4247/AM.2012.

ABB017

15

Review

Effects of Exercise on Patients with Endometrial Cancer

Tsui-Yun Yang and Tsui-Hsia Feng
School of Nursing, Chang Gung University, Kwei-Shan, Taoyuan 33333, Taiwan, Republic of China

Endometrial cancer is the most common gynecological cancer affecting post-menopausal women. It has been well documented that old age, estrogen overexposure, obesity and physical inactivity are major risk factors contributing to the development of endometrial cancer. Increased physical activity or exercise can alleviate diseaseand treatment-related symptoms and improve quality of life of cancer patients during and after treatment. However, few studies have been focused the effects of physical exercise for patients that were treated for endometrial cancer. This paper aims to provide an overview of the course and treatment of endometrial cancer, cancer- and treatment-related symptoms, and the effects of physical exercise. Key Words: endometrial cancer, exercise, cancer-related symptoms

Introduction
Endometrial cancer, also known as uterine cancer, is the most common gynecologic cancer affecting postmenopausal women (7, 20, 30). It has been the seventh most frequent cancer around the world, with variant incidence in different regions (3). Endometrial cancer ranks fourth in terms of incident cancers in women, after breast, lung, and colorectal cancers, and eighth in terms of age-adjusted mortality (30). In the United States, the National Cancer Institute estimates that 47,130 new cases and 8,010 deaths from endometrial cancer will occurr in 2012*. Although the incidence rate is lower in Taiwan as compared to the western populations, the number of cases is growing due to lifestyle changes, avalability of advanced diagnostic evaluations and skills, and increased aging of Taiwanese women. In 2007, the Cancer Registry Statistics Annual Report revealed that endometrial cancer in Taiwan ranked eighth in terms of incident cancers in women, and sixteenth in

terms of mortality in women#. Incidence of endometrial cancer in Taiwan has increased since 1980, and the estimated number of new cases of endometrial cancer in Taiwan in 2007 was 1,165 (10.26 per 100, 000 people) with variant mortality rate ranging from 8.5% to 15.7% since 1995 #. It is well documented that old age, estrogen overexposure, obesity and physical inactivity are the major risk factors contributing to the development of endometrial cancer (3, 7, 10-12, 20, 30). Literature review also reveals that increased physical activity or exercise can prevent endometrial cancer (16, 20). Moreover, increased physical activity or exercise can alleviate cancer- and treatment-related symptoms and improve quality of life of cancer patients during and after treatment (17, 18, 21, 29, 31, 32). However, literature rarely discusses the effects of physical exercise for patients that received treatment for endometrial cancer. The purpose of this paper is to provide an overview of the course and treatment of endometrial cancer, cancer- and treatment-related symptoms, and the effects of physical exercise.

Endometrial Cancer and Its Treatment

The major risk factors associated with developing endometrial cancer are prolonged, unopposed estrogen exposure and also tamoxifen treatment of breast cancer, possibly related to the unopposed estrogenic effect of tamoxifen on the endometrium (3). Therefore, prolonged menstruation, nulliparity, irregular ovulation, history of breast cancer, ovarian tumor or ovarian cancer, and estrogen-only replacement therapy are all associated with increased risk of developing endometrial cancer (7, 12, 30). Excessive fat consumption and overweight are important risk factors present in almost 50% of women with endometrial

*National Cancer Institute. Endometrial cancer. Retrieved from http://cancer.gov/cancertopics/types/endometrial on Feb. 29, 2012. # Bureau of Health Promotion, Department of Health, The Executive Yuan, Taiwan. Cancer Registry Statistics Annual Report, 2007, Taiwan, pages: 84-85, 2010. Corresponding author: Tsui-Hsia Feng, Lecturer, School of Nursing, Chang Gung University, 259 Wen-Hua 1st Road, Kwei-Shan, Taoyuan 33333, Taiwan, R.O.C. Tel: +886-3-2118800 ext. 5212, Fax: +886-3-2117700, E-mail: thf@mail.cgu.edu.tw Received: October 7, 2011; Revised: February 25, 2012; Accepted: March 3, 2012. 2012 by The Society of Adaptive Science in Taiwan and Airiti Press Inc. ISSN : 2076-944X. http://www.sast.org.tw

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cancer (3, 10, 11). Obesity causes insulin resistance, excessive ovarian androgen, anovulation, and chronic progesterone deficiency in premenopausal women and enhanced peripheral conversion of androgens to estrogens in postmenopausal women; consequently, the hormonal alteration stimulates endometrial cell proliferation, inhibits apoptosis, and promotes angiogenesis (7, 30). A woman with BMI above 25 kg/m2 doubles her risk of endometrial cancer, and triples her risk with a BMI above 30 kg/m 2 (11). Evidence showed that physical inactivity, high energy intake, blood pressure above 140/90 mmHg, and high serum glucose concentrations are BMI-independent risk factors related to endometrial cancer development (3, 7). Histologically, about 80% of endometrial cancers are endometrioid type carcinomas (type 1) which are typically hormone-sensitive, low stage, and have an excellent prognosis; whereas, type 2 endometrial cancers are high grade with a recurrence tendency, even in early stage (3, 7). According to the system of the International Federation of Gynecology and Obstetrics (FIGO), an endometrioid carcinoma of grade 1 consists of well-formed glands, with no more than 5% solid non-squamous areas (areas of squamous differentiation are not deemed to be solid tumor growth), and carcinomas of grade 2 consist of 6-50% and those of grade 3 of more than 50% solid non-squamous areas (3). The degree of tumor differentiation has an important impact on the natural history of endometrial cancer and on its treatment selection (34). Endometrial cancer is a surgically-staged disease, because clinical estimates and preoperative imaging of the extent are incorrect in over 20% of cases (3, 7). The most important prognostic features in endometrial cancer are the surgical FIGO stage, myometrial invasion, histological type, and differentiation grade (34). The FIGO stage reflects the 5-year survival, which varies according to series but is around 85% for stage I, 75% for stage II, 45% for stage III, and 25% for stage IV disease (3). A total abdominal hysterectomy and bilateral salpingo-oophorectomy with or without para-aortic pelvic lymphadenectomy would be the primary treatment selection if the endometrial cancer is well or moderately differentiated (34). Radiotherapy with external pelvic irradiation, vaginal brachytherapy, or combination of these modalities has been suggested for patients with stage IC and above (7). Chemotherapy and hormone therapy remain the treatment of choice for patients with advanced or recurrent endometrial cancer according to a recent published guideline in Taiwan and a consensus statement from Asian Oncology Summit in 2009 (34).

Symptom Experiences Related to the Endometrial Cancer and Its Treatment

Endometrial cancer presents with abnormal uterine bleeding in 90% of patients; thus, any vaginal bleeding in a postmenopausal woman warrants an initial evaluation for the possibility (7). A recent systematic review on the impact of treatment for gynecologic cancer patients found that diarrhea, followed by fatigue, insomnia, nausea, anorexia or loss of appetite, were the most experienced symptoms during external radiotherapy, but declined at 3 months after treatment (22). The symptoms or side effects associated with abdominal total hysterectomy and bilateral salpingooophorectomy for patients with endometrial cancers are temporal wound pain initially, permanent loss of menstrual function, infertility, and possible sexual dysfunction, especially in those with pelvic irradiation (5). About 50% of women with gynecologic cancers have problems with sexuality in the first year after treatment, and 40% have chronic difficulties (4). These treatment-related symptoms may include reduced sexual desire, lack of arousal and orgasm, diminished lubrication and sensation, premature menopause, loss of fertility, reduction in vaginal elasticity, a shortened vaginal cavity, vaginal dryness, atrophy and contraction, cystitis and occasionally urethral and rectal fistulas, which further inhibit the patients ability to resume satisfactory sexual functioning (23). Meanwhile, a prior report of a 12-year experience in endometrial cancer patients undergoing surgery with lymphadenectomy at initial surgery appeared to be at higher risk for new-onset symptomatic leg lymphedema, which may disturb the body image of patients as well as their physical activity (1). Besides vaginal atrophy, skin change, nausea, vomiting, diarrhea and abdominal cramps (flatulence) are often observed in patients with endometrial cancers receiving pelvic radiation therapy (27). A literature review suggested that 70% of the patients submitted to abdominal radiotherapy are at higher risk of developing vomiting and nausea (28). The symptoms of acute radiation enteritis, dominated by diarrhea, occur in more than 70% of patients undergoing pelvic irradiation and even 3-4 years after treatment (9, 36). Klee and Machin found that endometrial cancer patients who were free of disease experienced distressful symptoms of diarrhea, urinary frequency, voiding pain, tiredness fatigue, irritation in or around the vagina, and hot flushes even two years after receiving external radiotherapy, which correlated with poorest quality of life as compared to a matched population of healthy women (25).

TCOG Clinical Guideline for Endometrial Cancer. National Health Research Institute Taiwan: 2004.

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Moreover, Christman et al. in their study of the symptom experiences of women with cervical or uterine cancer undergoing combination of surgery and radiotherapy mostly found difficulty sleeping, followed by fatigue, diarrhea, anorexia and nausea, urinary frequency and dysuria, and vaginal discharge and perineal irritation during and 4 weeks after treatment (13). Similarly, Ahlberg et al. in their study of the symptom experience of patients with uterine cancer during radiotherapy found fatigue, loss of appetite, nausea/vomiting, diarrhea, and pain increasing significantly during the first three weeks of therapy, and continued after completing the therapy except for the pain (2). The investigators also found that radiation-induced fatigue has no relation to insomnia in these patients (2). Because endometrial cancer patients had rarely been diagnosed at late stage initially reports rarely mentioned chemotherapy-related symptoms in this patient population (34). However, they may experience chemotherapy-induced side effects if the cancer recurred (17). The problems with fatigue and chemotherapy-induced peripheral neuropathy are most complained (6, 19).

Exercise in Symptom Management for Patients with Endometrial Cancer

In previous animal and human studies, exercise has proved to have certain biological effects on angiogenesis promotion via upregulated vascular endothelial growth factor (VEGF) in elderly subjects, enhanced glucose uptake in skeletal muscle groups, and accelerated insulin and insulin-like growth factor1 (IGF-1) response in vasorelaxation, which prevent several chronic conditions seen in the elderly, such as, cardiovascular disease, hypertension, diabetes mellitus, cancer, and others (26, 33, 35). According to the suggestions from the US Department of Health and Human Service and several studies, a period of physical inactivity during and after treatment may cause the cancer patients decrease in cardiorespiratory fitness, bone loss and muscle atrophy, as well as worsening of glucose metabolism, insulin sensitivity, digestive function, immune function, and further cardiovascular risk factors (21, 29, 31) . Meanwhile, studies have suggested that strong positive effects of physical activity for cancer patients during treatment were mainly on the physiologic outcome (i.e. hemoglobin, hematocrit, albumin, etc.) and symptoms/side effects (17, 18, 31, 32). However, physical activity behavior, cardiorespiratory fitness, fatigue, quality of life, reduced body size, depression, anxiety, and

some mental problems showed less significant improvement from physical activity or exercise in these studies (17, 18, 31, 32). In addition, most studies about exercise interventions were in breast cancer patients and some were hampered by small sample sizes (31, 32). Because the process of obesity in breast cancer pathogenesis due to adiposity-induced alterations in circulating levels of sex steroids is similar to the endometrial cancer; therefore, the effects of exercise on breast cancer patients may extrapolate to the patients with endometrial cancer (3, 10). Obesity and physical inactivity, along with diabetes and hypertension showed a strong correlation with the development of endometrial cancer for women after certain age (16, 20, 30). However, a descriptive study of endometrial cancer survivors showed 72% were overweight (34%) or obese (38%), and 70% did not the minimum public exercise criteria; moreover, increased physical activity is not necessary for improvement of quality of life by controlling the patients body weight for endometrial cancer survivors; that is, both exercise and body mass index were independently associated with quality of life for these particular populations (14). Exercise in endometrial cancer survivors may lead to a better quality of life by improving physical fitness, controlling treatmentrelated side effects, reducing the risks of other chronic diseases, providing a positive distraction from distressing events, improving body image, and increasing social interaction (14). In conclusion, exercise has shown a number of promising benefits for patients with endometrial cancer. Studies found that duration and intensity of exercise also affect the angiogenesis in elderly subjects and suggested that regular physical activity with moderate intensity may preserve the angiothergenic properties and maintain the sufficient blood flow even at old age which further prevents from chronic diseases (i.e. diabetes, arthritis, cancer, etc.) (26). Several issues in future studies for this particular patient population should provide more evidence about the reason, dose, mode and frequency of exercise which are most beneficial to the patients during and after treatment, and how to prevent the side effects from the exercise interventions. A population-based study showed that most endometrial cancer survivors (76.9%) were interested in exercise program and actually preferred walking in a moderate intensity (24). It seems that moderate walking as one mode of aerobic exercise would be the first choice of the exercise interventions for endometrial cancer patients. Some barriers to the physical exercise and the intention to exercise also need to be considered, especially for

U.S. Department of Health and Human Service. Physical activity and health: a report of the surgeon general. National Center for Chronic Disease Prevention and Health Promotion. Washington DC: 1996.

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endometrial cancer patients with habituated sedentary lifestyle, obesity-related physical incapacity and cormobidities (i.e. diabetes, hypertension, arthritis, etc.), treatment-related symptoms, such as fatigue, chronic diarrhea, pain in the lower abdominal area, lower back, hip and thigh, as well as risks of developing lymphedema (8, 15).

Acknowledgments
This review paper was sponsored in part by the grant (CMRPG350991) from Chang Gung Memorial Hospital, Taoyuan, Taiwan.

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