Helping endometrial cancer survivors to live longer-and better

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ACCREDITATION

This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of CME2, Inc. ("cme²") and Contemporary OB/GYN. cme² is accredited by the ACCME to provide continuing medical education for physicians.

cme² designates this educational activity for a maximum of 1.0 AMA PRA Category 1 Credit(tm). Physicians should only claim credit commensurate with the extent of their participation in the activity.

TARGET AUDIENCE

Obstetrician/gynecologists and women's health practitioners.

EDUCATIONAL OBJECTIVES

After completing the following CME activity, the reader should be able to:

• Describe the role of obesity as a significant risk factor in the development of endometrial cancer, as increasing the risk of common comorbidities such as diabetes and heart disease, and explain the need to provide counseling on lifestyle interventions.
• Recognize the various responsibilities of the gynecologist as the primary-care physician in managing patients with endometrial cancer before and after surgery.
• Summarize the elements of posttreatment surveillance of endometrial cancer survivors following the National Comprehensive Cancer Network guidelines.
• Identify the risks and benefits of hormone therapy for postmenopausal symptoms of endometrial cancer survivors.

TO EARN CREDIT FOR THIS ACTIVITY

Participants should study the article, log onto http://www.modernmedicine.com, click on the "CME/CE Center" tab at the top of the page and type in keyword: COG112007. Participants will be taken to the activity, where they must pass a post-test and complete an online evaluation. After passing the post-test and completing the online evaluation, a CME certificate will be automatically generated. The release date for this activity is November 1, 2007. The expiration date is November 1, 2008.

DISCLOSURES

Editors Elizabeth Nissen, Paul Cerrato, and Julia Talsma, and Instructional Design Consultant Richard Currier, PhD, disclose that they do not have any financial relationships with any manufacturer in this area of medicine.

The manuscript reviewer discloses that he has no financial relationships with any manufacturer in this area of medicine.

Dr. Fader, Dr. von Gruenigen, and Ms. Gibbons disclose that they have no financial relationships with any manufacturer in this area of medicine.

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UNAPPROVED/OFF-LABEL USE DISCUSSION

Faculty may discuss information about pharmaceutical agents, devices, or diagnostic products that are outside of FDA-approved labeling. This information is intended solely for CME and is not intended to promote off-label use of these medications. If you have questions, contact the medical affairs department of the manufacturer for the most recent prescribing information. Faculty are required to disclose any off-label discussion.

Endometrial cancer (EC), the most common gynecologic malignancy in the United States, killed 3,750 women last year.¹ And more than 41,000 new cases were diagnosed during the same period.

A woman's lifetime risk of developing EC is 2.6%. Fortunately, most cases are early stage, with disease limited to the uterus, and appear to have an excellent prognosis (5-year survival of 90%). If early-stage low-grade disease is detected, it's tempting for physicians to think of EC patients as being "in the clear" after a hysterectomy and staging procedure. But don't let down your guard so fast. Recent studies show that although most women with EC are not dying from their cancers, they have a significantly increased risk of dying from other causes when compared with women without EC. Why, then, are EC survivors not living longer?

Obesity is a huge threat

Obesity is a significant risk factor for developing EC and also poses one of the greatest health threats to patients post-treatment. Approximately 70% to 90% of EC patients are obese, suffer from obesity- driven co-existing conditions like type II diabetes, hypertension, heart disease, osteoarthritis, and pulmonary disease, and require a comprehensive approach to medical care.^2,3 Researchers have shown that obesity increased the risk of EC by 450% and a sedentary lifestyle increased risk by 46%.⁴ As the US experiences an unparalleled rise in obesity rates, several large epidemiologic studies have linked obesity (body mass index [BMI] >30)-and especially morbid obesity (BMI >40)-with an increased rate of death from all causes.^5,6

Furthermore, obesity now contributes as much as smoking to overall cancer death.⁷ Women with a BMI greater than 40 have a 60% higher risk of dying from all cancers than women of normal weight. A report from the Gynecologic Oncology Group (GOG) showed that obesity also increases the risk of mortality (but not disease recurrence rates) in women after EC.² A similar report suggests that obese EC survivors who also have diabetes have a decreased life expectancy when compared with their nonobese, nondiabetic counterparts with EC.⁸

WHILE OBESITY INCREASES the risk of recurrence and cancer death in patients with breast and colon cancer, the good news for women with EC is that it doesn't appear to pose the same risk of cancer-related mortality in them. But the bad news for EC patients is that they are more likely to die earlier from causes other than cancer when compared with age-matched women without EC, especially of obesity-related co-existing conditions like diabetes, hypertension, and cardiovascular disease.⁷ There is considerable evidence that healthy lifestyle changes among women with colonic or breast malignancies lower the risk of cancer recurrence and improve overall survival.⁹ Unfortunately, while breast cancer survivors seem motivated to modify their diets and increase their physical activity levels after treatment, most EC survivors are not in fact adopting healthier lifestyle choices.

Certainly, women with breast and EC have similar posttreatment goals, as shown in a study of 51 breast and gynecologic cancer survivors in which the most common health-related goals after treatment were improving physical activity (54%), losing weight (21%-22%), and eating a better diet (16%-22%).¹⁰ However, studies show that EC patients are not achieving these goals posttreatment. Can physicians do more to encourage EC patients to adopt healthier lifestyles, and will this result in improved outcomes for patients? We'll look at several sample scenarios to answer those questions.

The gynecologist's role and the teachable moment

Many EC patients receive initial cancer care from a gynecologic oncologist.¹¹ However, generalist gynecologists often establish long-term relationships with their patients and families and can

1 help with primary surgical management,

2 ensure continued surveillance for cancer recurrence,

3 provide preventive care,

4 coordinate multidisciplinary care for women with comorbidities, and

5 help their patients make informed decisions about hormone therapy (HT) and sexual health options both during and after treatment.

As primary-care physicians, gynecologists also have an opportunity to address health-related lifestyle modifications in the post-cancer treatment period-the "teachable moment" when cancer survivors are more likely to be interested in modifying their lifestyles (see "Finding that teachable moment".)

Cancer surveillance

A 64-year old G0 woman, diagnosed with stage IA, grade 1 endometrioid adenocarcinoma of the endometrium by a staging procedure 2 years ago, is referred to her primary gynecologist for follow-up care. Her cancer was surgically treated by a gynecologic oncologist and she has undergone pelvic exams every 3 to 4 months and Pap smears every 6 months with no evidence of recurrent disease. How should the gynecologist approach continued surveillance?

Depending on the extent of disease detected at surgery, patients can be offered no further treatment or adjuvant therapy with either radiation or a combination chemotherapy and radiation regimen. Treatment-related considerations are beyond the scope of this article, but goals of posttreatment surveillance are early recognition and treatment of potentially curable, localized recurrences, detection of symptoms of metastatic disease, and diagnosis and management of treatment-related effects. The greatest emphasis on surveillance is within the first 2 to 3 years after primary treatment, which is when most recurrences develop.^12,13 Surveillance guidelines following treatment of EC (Table 1) are available from the National Comprehensive Cancer Network (NCCN).^14,15

Although follow-up care for EC patients can be shared by a treatment team, one physician should be formally responsible for coordinating a patient's care. It's our practice to follow patients with early-stage disease in a specialty practice for at least 2 years after diagnosis, but patients may be followed by a gynecologist experienced with posttreatment surveillance and examination of an irradiated vaginal cuff or pelvis. But if you suspect a cancer recurrence, refer your patient immediately to a gynecologic oncologist.

All postmenopausal women, including EC survivors, should undergo regular screening for breast and colorectal cancer. Moreover, EC survivors are at increased risk for developing secondary malignancies-especially if they have a history of obesity or diabetes-or both-and should be so counseled.¹⁶ Women with a strong family history of colon and/or EC or with a personal history of either malignancy before age 45 may have a familial cancer syndrome (such as hereditary nonpolyposis colorectal cancer-HNPCC). Consider referring them to a geneticist. Finally, be sure to screen EC survivors annually for osteoporosis with a DEXA scan. Postmenopausal status (surgical, natural, or chemotherapy-induced) and diabetes all significantly increase the risk of osteoporosis.¹⁷

Comorbidities and lifestyle intervention trials

A 59-year old G1, P1 underwent a hysterectomy, bilateral salpingo-oophorectomy, and staging procedure for stage IB, grade 2 EC. After counseling regarding observation versus postoperative brachytherapy, the patient opts for observation. Coexisting conditions include morbid obesity (BMI 52), type 2 diabetes, and sleep apnea. Other than intensive surveillance for cancer recurrence and screening for secondary malignancies, what other recommendations should the physician make at this time?

Studies show that breast and colorectal cancer survivors who incorporate healthy dietary and exercise changes improve their health-related quality of life (QoL) and prolong their QoL and life expectancy (Table 2).^18,19 But when it comes to EC, there are few studies related to long-term survival, particularly in the areas of health or lifestyle outcomes and their modulation by common risk factors. However, we do know that early-stage EC survivors are primarily dying of obesity-driven conditions and substantial data from large trials suggest that women who make healthy lifestyle modifications like losing weight, consuming a diet low in animal fat and rich in fiber and vegetables, and incorporating cardiovascular exercise can improve their QoL and survival.^20-22

Research shows that an EC patient's QoL is affected by lifestyle, physical well-being, and education level.²³ In a recent study of 386 EC survivors who were surveyed about exercise and BMI, investigators showed that lack of exercise and excess body weight exacerbated treatment-related declines in QoL in EC survivors.³ Roughly 70% of the women surveyed were obese and were not meeting public health exercise guidelines. Multivariate analyses showed that healthy, fit EC survivors reported significantly better QoL than did unfit, obese survivors and that both exercise (P<0.001) and BMI (P<0.001) were independently associated with QoL.

von Gruenigen and colleagues conducted a prospective observational trial in 43 newly diagnosed EC patients-86% of whom were obese-which assessed changes in diet, exercise, and complementary medicine use preoperatively and 6 months post-operatively.²⁴ No study interventions were performed (e.g., nutritional counseling) to modify behaviors. Weight, exercise, and fruit and vegetable intake did not change over time; however, complementary/alternative medicine use increased significantly at 6 months (P=0.008). Although small, this study highlighted an important observation that may apply to most EC patients-without intervention, women with EC who are sedentary or obese are unlikely to modify their exercise and nutrition behaviors after diagnosis and treatment. Rather, they turned to alternative therapies, and noted primarily doing so to cope with effects from medical treatments. This may indicate that physicians are not adequately counseling patients on the relationship between obesity, EC, and mortality or addressing medical treatment-related concerns.

The same authors performed a follow-up prospective study in which 45 overweight and obese EC survivors were randomized to receive lifestyle counseling focused on weight loss, increased physical activity, and healthy eating behaviors versus usual care for 6 months.²⁵ Some 60% of patients had either a new medication started or a hospitalization related to obesity during the study period. At 1 year, the intervention group lost 3.5 kg compared with a 1.4-kg gain in the control group (P=0.018) and increased their physical activity by 16.4 metabolic equivalents (METS) compared with a drop of 1.3 METS in the control group (P=0.002). Results indicate that a lifestyle intervention program in EC survivors is feasible and can result in sustained behavior change and weight loss over 1 year.

Much remains to be learned about the role of nutritional factors and physical activity in survival after a diagnosis of EC. While discussing the cancer itself with patients is critical, you should also focus on the impact of obesity and cardiovascular and diabetic comorbidities on patients' QoL and survival. Be sure to address weight management, physical activity, and adherence to cardiovascular and diabetic treatment recommendations and facilitate their referral to specialists in these areas.

Hormone therapy and sexual health

A 51-year old G2,P2 woman underwent a staging surgery for EC and was diagnosed with stage IA, grade 2 disease. After several months of observation, she complains that since the surgery, she has experienced uncomfortable hot flashes and vaginal dryness. She is also concerned about developing osteoporosis, as her mother and sister were both diagnosed with it. What are her options? Is it safe to offer HT?

Estrogen therapy (ET) for EC survivors remains controversial. Because endometrial adenocarcinoma is considered an estrogen-responsive malignancy, women successfully treated by hysterectomy, with or without adjuvant therapy, have usually been denied HT for fear of increasing the risk of relapse. However, it has never been proven that there is a higher recurrence rate in EC survivors treated with ET after hysterectomy. On the contrary, the preponderance of retrospective studies and one prospective trial have shown no increase in recurrence or cancer-related deaths in HT-treated women with a history of early-stage EC.^26,27 However, ET trials in postmenopausal women without a history of cancer have shown an increased risk of breast cancer.²⁸

Nonetheless, menopausal symptoms such as hot flashes, vaginal dryness, dyspareunia, and osteoporosis leading to fractures adversely affect QoL of both EC survivors and postmenopausal women in general. Expert opinion from an NCCN consensus panel suggests that ET is reasonable for patients at low risk for tumor recurrence, but you should individualize treatment after discussing risks and benefits.¹³ If EC survivors have no vasomotor symptoms, selective estrogen-receptor modulators (SERMs) can be an acceptable alternative to help protect women from osteoporosis and lipid abnormalities.²⁹ Although not studied specifically in EC survivors, reports in breast cancer survivors suggest that transdermal clonidine, venlafaxine, or selective serotonin reuptake inhibitors can be reasonable alternatives for treating hot flashes or night sweats.^30-32

FINALLY, there are few studies on post-treatment sexual adjustment and its impact on QoL in EC patients. A survey of 20 women treated for endometrial or cervical cancer revealed that most had difficulties with intimacy and feeling "feminine."³³ A similar study of 45 EC patients surveyed with the Sexual Activity Questionnaire³⁴ found that lack of interest and fatigue accounted for 22.8% of patients not engaging in sexual activity.²⁵ These results highlight the importance of communication among health professionals, patients, and partners. Provision of information, support, and rehabilitation (such as using vaginal dilators and lubrication for vaginal stenosis after radiation therapy) is suggested.

In summary, QoL has become quite important to the ever-growing number of long-term endometrial cancer survivors. With most EC patients living more than 5 years after diagnosis, gynecologists as well as oncologists have the challenge of expanding their focus from acute cancer care to managing longer-term health problems.²⁰ Although larger randomized trials are needed to determine how weight, comorbidities, and lifestyle modification affect EC outcomes, studies thus far show that patients benefit from weight loss and other healthy lifestyle interventions. Care for EC survivors should go way beyond surveillance for recurrent disease. For all patients, health maintenance, sexual health, and lifestyle factors should be considered, as well. The gynecologist plays an important role in facilitating this care. By continuing our techniques of detecting EC early, providing timely treatment, and helping patients incorporate healthier habits into their lifestyles, we can look forward to healthier, longer-lived EC survivors.

DR. FADER is a Clinical Fellow in Gynecologic Oncology at the Cleveland Clinic and University Hospitals of Cleveland, Cleveland, Ohio. MS. GIBBONS is a Statistician, and DR. VON GRUENIGEN is an Associate Professor, Department of Obstetrics and Gynecology, University Hospitals, Case Medical Center; Cleveland, Ohio.

This research was supported by a grant from the Lance Armstrong Foundation.

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