Diljeet K. Singh and Vivian E. von Gruenigen
The World Health Organization (WHO) defines health broadly as “a state of complete physical, mental and social well-being and not merely the absence of disease or infirmity.”1 This far-reaching definition reminds us of the powerful influence we can have as practitioners not only on the number of days our patients live but also on the quality and depth of their lives. For many patients, a cancer diagnosis provides an opportunity to examine their mortality and their lives. For some, this may enable them to make considerable health-supporting changes in their lifestyle including discontinuing tobacco use, improving their diet, and adding physical activity and stress management techniques to their health regimens. Others may find themselves exploring their spiritual beliefs and examining other aspects of their life. As health care providers, we can support our patients in their efforts to achieve their optimal health throughout the life cycle.
An understanding of integrative oncology, quality of life (QOL), supportive and palliative care, symptom management, and end-of-life (EOL) care can inform our ability to address our patients’ global health needs (Figure 22-1).
FIGURE 22-1. Holistic care for the gynecologic oncology patient.
INTEGRATIVE ONCOLOGY
Definitions
The National Center for Complementary and Alternative Medicine (NCCAM) at the National Institutes of Health defines complementary, alternative, and integrative medicine (CAM) as follows: Complementary medicine refers to use of CAM together with conventional medicine. Alternative medicine refers to use of CAM in place of conventional medicine. Integrative medicine refers to a practice that combines both conventional and CAM treatments for which there is evidence of safety and effectiveness. Practitioners describe integrative oncology as both a science and a philosophy that focuses on the complexity of the well-being of cancer patients and proposes a multitude of approaches to accompany conventional therapies to facilitate health.2 In addition, integrative oncologists strive to support the innate healing abilities of the individual, using techniques for self-empowerment, individual responsibility, and lifestyle changes that could potentially reduce both cancer recurrence and second primary tumors. Integrative medicine includes biologically based practices (eg, diet, dietary supplements, herbs), mind-body medicine (eg, guided imagery, hypnosis, meditation, stress management), manipulative or body-based practices (eg, massage therapy, chiropractic, reflexology), energy medicine (eg, acupuncture, qigong, Reiki, yoga), and whole system approaches (eg, Ayurveda, traditional Chinese medicine [TCM], homeopathy) (Table 22-1).
Table 22-1 Integrative Modalities
Biologically based practices
Diet, dietary supplements, herbs
Mind-body medicine
Guided imagery, hypnosis, meditation, stress
management, biofeedback, social support
Manipulative or body-based practices
Massage therapy, chiropractic, reflexology
Energy medicine
Acupuncture, qigong, Reiki, yoga, healing touch
Whole system approaches
Ayurveda, traditional Chinese medicine, homeopathy
For a number of reasons, ongoing tension exists between some aspects of integrative medicine and conventional medicine. Although the impact of diet, exercise, and stress management techniques on health is relatively well accepted, limited research and differing philosophical underpinnings have fostered distrust and knowledge gaps among conventional providers, which contribute to reluctance on the part of patients to discuss their usage with their providers. Data from well-conducted trials on the risks and benefits of complementary modalities are limited for several reasons. First, the NCCAM was only relatively recently established in 1999 as a consistent source of guidance and funding for research and training. Researchers have also identified lack of quality and substantial variability of dietary supplements as significant challenges to conducting research. The US Food and Drug Administration regulates dietary supplements as foods, not drugs, and thus does not analyze the content of dietary supplements. Whereas synthetic, single-entity drugs are relatively easy to characterize, the complexities of herbal preparations and our incomplete knowledge regarding the active components hinder research efforts. Traditional evidence-based medical research focuses on 1 variable and its impact on 1 outcome. By definition, integrative approaches imply a whole system with multiple component parts that work together toward the maximum benefit of the patient. Thus, the best-suited research programs would evaluate a whole systems approach to patients. Studies and their analysis might include psychological interventions, physical exercises, nutritional variations, and combinations of botanicals. For example, in a series of work with prostate cancer patients, Ornish et al3 used a mixed-interventions approach described as comprehensive lifestyle changes including nutritional changes, physical activity, and meditation and found decreases in prostate-specific antigen and cell and serum level changes thought to inhibit cancer progression.
Usage
The widespread use of CAM represents a challenge and an opportunity to our field; we must balance safety with our commitment to allow our patients to avail themselves of all potentially beneficial modalities. In 2008, the National Center for Health Statistics indicated that 38% of all Americans use some form of CAM.4 A 2005 Institute of Medicine report detailed this trend and reported that Americans were spending at least $27 billion out of pocket for CAM products and services.5 Use of CAM is particularly common among people with cancer. Studies indicate that up to 80% of all cancer patients use some form of CAM most commonly including acupuncture, massage, yoga, energy healing, TCM, Ayurveda, mind-body interventions, and a wide variety of vitamins, mineral supplements, antioxidants, and herbs.6 Studies reveal that 40% to 70% of patients do not report CAM use to their physicians for a wide variety of reasons and that most patients are willing to discuss CAM use with their physicians, but they are concerned that their physician will not understand, approve of, or have interest in these modalities. Furthermore, although increasing numbers of physicians express open attitudes toward CAM therapies, they may be hesitant to discuss this with patients because of their lack of knowledge and a desire not to appear uninformed. A survey of ovarian cancer patients revealed significant use of herbs and a perceived need among patients for guidance from their physicians.7
Several concerns regarding the use of herbs and antioxidants are relevant to providers of women with a gynecologic malignancy. Quality of herbal preparations has not been well governed, and contamination of preparations has been reported. However, reported cases of complications with herb use are quite rare, and with trained guidance, safe, effective products can be identified. Antiplatelet effects and prolongation of coagulation parameters can theoretically occur with ginkgo biloba, garlic, ginseng, fish oils, vitamin E, dong quai, and feverfew. Holding these herbs before surgery is reasonable; it is unclear whether their potential bleeding effects warrant prohibiting their use during chemotherapy. Neuroprotective effects of vitamin E may outweigh the theoretical risks (see Symptom Management section). Cardiovascular effects of ephedra include tachycardia, hypertension, and palpitations, and pharmacologic doses of garlic may cause hypotension. Hypoglycemia has been reported with ginseng. Pharmacodynamic herb–drug interactions include potentiating the sedative effect of anesthetics by kava and valerian, and these may be held perioperatively as well. St. John’s wort induces cytochrome P450, leading to increased metabolism of many drugs including warfarin, irinotecan, cyclosporine, oral contraceptives, digitalis, midazolam, lidocaine, and calcium channel blockers. Echinacea, goldenseal, and licroice may inhibit cytochrome P450, thus increasing circulating concenetrations of these same medications. Herbs that induce or inhibit drug metabolism should be used with caution during chemotherapy, as should other drugs known to alter metabolism.
Substantial controversy exists regarding the safety of supplemental antioxidant administration during chemotherapy and radiation.8 Some practitioners have raised the concern that antioxidants may decrease the efficacy of chemotherapy by interfering with its mechanism of action. Others site data that antioxidant supplements are useful in conjunction with chemotherapy because they enhance the efficacy of the chemotherapy and alleviate toxic side effects, allowing patients to tolerate chemotherapy for the full course of treatment and possibly at higher doses. From the 19 randomized controlled trials of antioxidant use during chemotherapy reviewed by Block et al, no evidence was found that supported concerns that antioxidant supplementation given with chemotherapy diminished the efficacy of the chemotherapy in study populations comprising mostly advanced or relapsed patients.9 In contrast, 17 of the 19 trials included in this review showed a statistically significant advantage or nonsignificantly higher survival and/or treatment response in patients given antioxidants. General and neurologic toxicities were also improved by antioxidant supplementation.
IMPACT OF LIFESTYLE ON GYNECOLOGIC CANCER
Multiple aspects of lifestyle impact on cancer risk and prognosis, including stress, social support, physical activity, and nutrition. Researchers postulate that stress-induced immunosuppression or dysregulation may contribute to the development and progression of malignancy. For example, in ovarian cancer patients, depressed and anxious mood is associated with a greater impairment of the cellular immune response and an increase in tumor progression.10Stress can be a cofactor for the initiation and progression of cancer. The catecholamine stress hormone norepinephrine may influence tumor progression by modulating the expression of factors implicated in angiogenesis and metastasis.11 Strategies to address stress in cancer patients include relaxation training, meditation, graded exercise, yoga, tai chi, and other mind-body interventions that induce the relaxation response. Social isolation is associated with an increased risk of death from cancer; thus, support groups and social connection can benefit cancer patients.
Weight, diet, and exercise are interrelated and modifiable risk factors for many diseases including cancer. Risk factors for endometrial cancer include obesity and sedentary lifestyle. Half of all endometrial cancers in postmenopausal women are attributable to being overweight (body mass index 
or obese 
. In a study of 1.2 million women enrolled in the Million Women Study in the United Kingdom, risk of endometrial cancer in obese women was almost triple that of normal-weight women.12 Data from more than 32,000 women participating in the Women’s Health Study confirmed the relationship between BMI and risk of endometrial cancer.13 Women reporting any vigorous activity had lower risk than those reporting none. A large, prospective cohort study of more than 250,000 women from 9 European countries found little association between physical activity and endometrial cancer risk, although a potential risk reduction in premenopausal women was identified.14 Data from the National Institutes of Health–American Association of Retired Persons Diet and Health Study of more than 100,000 women found a dose-response relationship between vigorous activity and endometrial cancer risk but no association with light/moderate, daily, routine or occupational physical activities. The relationship between physical activity and endometrial cancer risk was also examined in the American Cancer Society Cancer Prevention Study II Nutrition Cohort of more than 40,000 postmenopausal women.15 They found that light and moderate physical activity were associated with lower endometrial cancer risk, although BMI attenuated the association. Physical activity was strongly associated with reduced risk in overweight and obese women in this study. The extent to which differences in level of physical activity contribute to endometrial cancer risk is not clear. In contrast, the relationship with BMI is unambiguous. Regardless of the direct effect of physical activity on endometrial cancer risk, women should be encouraged to maintain appropriate levels of physical activity to help maintain body weight.
BMI may influence patient outcomes and survival. In an analysis of nearly 400 early-stage endometrial cancer patients from a randomized trial of surgery with or without adjuvant radiation therapy, mortality was increased in obese patients and in morbidly obese patients, compared with lighter-weight women.16 In an analysis of patients with advanced or recurrent endometrial cancer from 5 Gynecology Oncology Group (GOG) trials who had been treated with adjuvant chemotherapy, no overall significant associations between progression-free survival (PFS) and BMI were detected. However, increased BMI was significantly associated with an increased risk of death in women with stage III/IV endometrial cancer, but not in patients with recurrent disease. Although some endometrial cancer patients gain weight after diagnosis, the effect of this weight gain on recurrence or mortality is unknown.
A recent review and meta-analysis examined the relationship between consumption of a high glycemic index or glycemic load (GL) diet and endometrial and ovarian cancer.17 The estimates for endometrial cancer showed an increased risk for high GL consumers, which was further elevated in obese women. Only 2 studies examined ovarian cancer, and results also indicate positive associations for GL.
Data evaluating obesity as a risk factor for epithelial ovarian cancer have been mixed. In a recent meta-analysis of 28 eligible studies, 24 studies reported a positive association between obesity and ovarian cancer, and in 10 studies, this reached statistical significance.18 In the European Prospective Investigation Into Cancer and Nutrition cohort of more than 200,000 women, the associations of measured anthropometric factors, including general and central adiposity and height, with ovarian cancer risk were evaluated with attention to menopausal status and specific histologic subtypes. There were approximately 600 incident cases of primary, malignant, epithelial ovarian cancer diagnosed during a mean follow-up of 9 years. Compared to normal-weight women, obesity was associated with an excess ovarian cancer risk for all women combined and for postmenopausal women, although the association was weaker for premenopausal women.19 Other studies have analyzed the relationship between obesity and ovarian cancer in regard to the duration of obesity. A study of Danish women diagnosed with ovarian cancer found that women who had been overweight during the previous 5 years had an increased risk of death compared with normal-weight women. A prospective study in China of women diagnosed with ovarian cancer also found that increased BMI 5 years prior to diagnosis was associated with reduced survival. A retrospective US study of advanced-stage ovarian cancer patients noted that obesity (BMI > 25 kg/m2) was independently associated with shorter disease-free survival and overall survival (OS).20 These studies suggest that overweight/obesity is associated with reduced survival from ovarian cancer; however, the role of physical activity and benefits of modifying weight after diagnosis are not addressed in these studies.
If weight is a poor prognostic indicator, it may be postulated that these patients perhaps are receiving subtherapeutic treatment. Inconsistencies in dosing chemotherapy for obese patients have included use of body surface area, dosing at ideal body weight, dose capping, and differing measurements of renal function, all of which can underestimate dose and consequently negatively influence survival. However, in the Scottish Randomized Trial in Ovarian Cancer I study, in which more than 1000 patients received front-line chemotherapy, BMI was not associated with PFS, OS, or completeness of debulking surgery.21 In a separate study of nearly 800 advanced ovarian cancer patients, no association between prechemotherapy BMI and survival was observed. Weight gain was associated with improved survival; however, 50% of the patients had a BMI of < 25 kg/m2, which would include women who were underweight and likely to benefit from weight gain.
Diet and Cancer Prevention
Studies of diet, nutrition, and cancer risk are restricted by retrospective collection of data, difficulty in correlating specific nutrients in food diaries, and the limitations of epidemiologic studies. In addition, advocates of integrative health approaches have objected to the reductionism of studying specific nutrients (vitamin A and β-carotene) instead of whole foods (yellow and orange fruits and vegetables), where the interactions of food components may be important. A holistic option is to study regional diets such as the Mediterranean diet.
Mediterranean Diet
The concept of the Mediterranean diet as a healthy diet was developed in the 1950s and referred to dietary patterns found in olive-growing areas of the Mediterranean region (Table 22-2). Although countries around the Mediterranean basin have different diets, religions, and cultures, common dietary characteristics have been identified and studied. The following scale was developed to determine adherence: (1) high monounsaturated-to-saturated lipid ratio, (2) high consumption of fruits, (3) high consumption of vegetables, (4) high consumption of legumes, (5) high consumption of cereals, (6) moderate to high consumption of fish, (7) low consumption of meat and meat products, (8) low to moderate consumption of milk and dairy products, and (9) moderate consumption of ethanol, mostly in the form of wine at meals. Many epidemiologic studies have demonstrated reduced risks of overall mortality, cardiovascular diseases, and several common neoplasms in adherents of the Mediterranean diet. A recent meta-analysis showed that increased adherence to the Mediterranean diet was associated with a significant reduction of overall mortality, cardiovascular incidence or mortality, cancer incidence or mortality, and neurodegenerative diseases.22 Mechanistically, researchers have proposed that the health benefits of this diet are based on bioactive compounds and their interactions, specifically monounsaturated-to-saturated fatty acid ratio, dietary fiber, antioxidant capacity of the whole diet, and phytosterol intake.
Table 22-2 Components of Mediterranean Diet
Omega-3–containing fats (olive oil, fish, nuts)
Protein predominantly from plant and fish sources
High consumption of fruits and vegetables
Low consumption of meat
Low to moderate consumption of dairy
Moderate consumption of red wine with meals
La Vecchia examined the relationship between the gynecologic cancers and specific components of the Mediterranean diet.23 He found a significant decreased risk for endometrial and ovarian cancer when comparing lowest vegetable intake to highest. The risk for ovarian cancer was statistically decreased for women with an increase of 1 g/wk of omega-3 fatty acids (found in fish and olive oil). Highest consumption level of whole grain foods was associated with decreased risk of endometrial and ovarian cancer. Previous work by this group also showed an increase in risk of both endometrial and ovarian cancer associated with ≥ 7 servings of red meat compared with consumption of ≤ 3 servings per week.
Individual Dietary Components
Additional work has evaluated the relationship between specific dietary components and gynecologic malignancies. A review of the literature on variation in meat and fish intake found that low consumption of processed meat and higher consumption of poultry and fish may reduce the risk of ovarian cancer.24 In contrast, high fish intake was associated with a reduced risk of ovarian cancer, and a frequent intake of poultry was associated with borderline significant reductions in risk of ovarian cancer. A systematic review of the role of diet on the risk of human papillomavirus (HPV) persistence and cervical neoplasia was conducted and included 23 observational studies and 10 randomized clinical trials.25 The studies on HPV persistence showed a possible protective effect of fruits, vegetables, vitamins C and E, β- and α-carotene, lycopene, lutein/zeaxanthin, and cryptoxanthin.
An association between decreased vitamin D levels and increased rates of cancer has been described. Researchers have postulated that the known north-south gradient in age-adjusted mortality rates of ovarian cancer in the United States are attributable to lower solar irradiance and thus lower serum vitamin D levels. In support of this, laboratory findings have suggested that low levels of vitamin D metabolites could play a role in the etiology of ovarian cancer. The association of solar ultraviolet B irradiance, stratospheric column ozone, and fertility rates at age 15 to 19 years with incidence rates of ovarian cancer in 175 countries was examined. Age-adjusted ovarian cancer incidence rates were highest in countries located at higher latitudes. A review of the literature found that approximately half of the ecologic and case-control studies reported reductions in incidence or mortality of ovarian cancer with increasing geographic latitude, solar radiation levels, or dietary/supplement consumption of vitamin D, whereas the other half reported null associations with ovarian cancer risk.26 In addition, no overall risk reduction was seen with increasing dietary/supplement consumption of vitamin D or with plasma levels of vitamin D prior to diagnosis; however, vitamin D intakes were relatively low in all studies. A serum study was performed to clarify the mixed data from ecologic studies. A case-control study of more than 7000 subjects from the National Health and Nutrition Examination Surveys demonstrated that ovarian cancer patients were 3 times more likely to have low serum vitamin D. These authors concluded that deficiency in vitamin D provides an etiologic link between the long-known ecologic findings regarding latitude.27
Botanicals
Several botanicals are being investigated as agents to inhibit cancer development; they include green tea, curcumin, Astragalus, and resveratrol. A systematic review of publications on green tea research concludes that green tea may have beneficial effects on cancer prevention and that further studies, such as large and long-term cohort studies and clinical trials, are warranted. Curcumin, a component of turmeric or curry powder, has been shown to downregulate several pathways of cancer initiation and promotion. Oral curcumin is well tolerated and has biological activity in some patients with pancreatic cancer. The dried root of Astragalus membranaceus (huang qi), a traditional Chinese herbal medicine, demonstrated improvements in survival, tumor response, and performance status in a meta-analysis of randomized trials of almost 3000 lung cancer patients on platinum-based chemotherapy.28 Resveratrol is a polyphenol found in numerous plant species, including grapes, that has been shown to possess chemopreventive properties against several cancers through inducing apoptosis. Additional studies of these agents in gynecologic cancer are warranted.
Researchers analyzed the association between intake of 5 common dietary flavonoids and the incidence of epithelial ovarian cancer in more than 60,000 women in the Nurses’ Health Study.29 Although no clear association was found between total intake of the 5 flavonoids and ovarian cancer, there was a significant 40% decrease in ovarian cancer incidence for the highest versus lowest quintile of kaempferol intake and a significant 34% decrease in incidence for the highest versus lowest quintile of luteolin intake. An inverse association with consumption of nonherbal tea and broccoli, the primary contributors to kaempferol intake in our population, further supported this association. A study of epithelial ovarian cancer patients in China showed that habitual green tea intake was protective, and the benefit was dose- and duration-dependent. A recent prospective cohort study in more than 60,000 Swedish women followed for more than 15 years provided evidence that green tea intake reduced the risk for the development of epithelial ovarian cancer in a dose-dependent manner. A case-control study of diet and ovarian cancer in western New York involving ovarian cancer cases and controls found that compared with women in the lowest quintile of intake, reduced risks were observed for women in the highest quintile of intake of dietary fiber (57% decrease), carotenoids (67% decrease), stigmasterol (58% decrease), total lignans (57% decrease), vegetables (53% decrease), and poultry (55% decrease).
Epidemiology studies have reported associations between increased soy intake and decreased risk of endocrine-related gynecologic cancers. Myung et al30 performed a meta-analysis examining the relationship between soy food intake and the risk of endometrial cancer and ovarian cancer. Compared with the lowest soy intake, the highest soy intake group had a 39% decrease in risk of all endocrine-related cancers, a 30% decrease in the risk of endometrial cancer, and a 48% decrease in risk of ovarian cancer. A case-control study of 500 women with endometrial cancer evaluated the associations between dietary intake of 7 specific compounds representing 3 classes of phytoestrogens (isoflavones, coumestans, and lignans) and risk. When comparing highest to lowest intake groups, isoflavone intake was associated with a 41% decrease in risk. In postmenopausal women, protection from isoflavones was even stronger, and a 43% reduction in endometrial cancer risk was also seen for lignan intake. Obese postmenopausal women consuming relatively low amounts of phytoestrogens had a 7-fold increase in the risk of endometrial cancer.
Diet and Cancer Prognosis
There is a paucity of research regarding nutrition and prognosis in ovarian cancer patients. In a longitudinal study of more than 300 women with ovarian cancer, longer survival was associated with total fruits and vegetables and vegetables separately. Subgroup analyses showed only yellow and cruciferous vegetables to significantly favor survival. In a population-based cohort of more than 600 women with epithelial ovarian cancer followed for up to 5 years, death was reduced in women who reported higher intake of vegetables and cruciferous vegetables. Inverse associations were seen between protein, red meat, and white meat and survival. There are no published studies of diet and endometrial cancer survival.
Regarding the relationship between individual dietary components and cancer prognosis, research has been done on vitamin D, green tea, and selenium. Studies in Norway and England found that individuals diagnosed with any cancer in summer or fall, when serum 25-hydroxyvitamin D levels are highest, had a milder clinical course and longer survival than those diagnosed in winter or spring. However, there are no vitamin D studies focused on gynecologic cancer survival after diagnosis. A small cohort study following more than 200 women with epithelial ovarian cancer demonstrated that habitual green tea consumption caused a significant dose-dependent increase in survival rate. Researchers evaluated the impact of randomized selenium supplementation in more than 30 patients with ovarian cancer undergoing chemotherapy. At 3 months, patients had significant increases in their white blood cells. After 2 to 3 months of selenium, significant decreases in hair loss, abdominal pain, weakness, and loss of appetite were noted among selenium-supplemented patients. Thus, promising data demonstrate the need for additional research to evaluate the potential for dietary modification and supplementation to improve survival and side effects in women with gynecologic malignancies.
Lifestyle and Quality of Life
Lifestyle decisions regarding nutrition, physical activity, tobacco use, and stress management not only affect cancer prevention and prognosis, but may also enhance QOL and improve patient outcomes. Physical activity may improve QOL, morbidity, and mortality in ovarian cancer patients.31 A study examining ovarian cancer survivors who were on and off active treatment found that those meeting public health guidelines for physical activity had lower self-reported levels of fatigue and better scores for peripheral neuropathy, depression, anxiety, and sleep quality than women not meeting guidelines. An additional study of women undergoing gynecologic surgery found that baseline characteristics such as physical and mental health, age, and body weight affect QOL scores. Therefore, regular physical activity may enhance survival by increasing QOL and improving ability to tolerate surgery and chemotherapy.
A recent study enrolled newly diagnosed ovarian cancer patients receiving adjuvant intraperitoneal (IP) or intravenous (IV) chemotherapy to a QOL lifestyle intervention trial.32 Patients were counseled in physical activity and nutrition quality. Assessments were obtained at entry to the study, during therapy (cycle 3), and after chemotherapy. Walking is the preferred mode of exercise for ovarian cancer patients. The median number of steps during the week of chemotherapy administration was less than 5000; 1 week after chemotherapy, steps increased to nearly 6000; and 2 weeks after chemotherapy, steps increased by nearly 5300. Steps were lowest after the first cycle of chemotherapy. QOL and emotional and functional well-being scores increased linearly during each cycle of chemotherapy. Therefore, it is feasible for ovarian cancer patients on adjuvant chemotherapy to increase physical activity that may improve QOL.
Lack of exercise and obesity are associated with lower QOL in endometrial cancer survivors. A survey of nearly 400 endometrial cancer survivors found that lack of exercise and excess body weight were associated with lower QOL. Approximately 70% of the women surveyed were obese and were not meeting public health exercise guidelines. Analyses showed that both exercise and BMI were independently associated with QOL. Another survey of 120 endometrial cancer survivors demonstrated that pain and fatigue decreased while physical functioning increased with physical activity. von Gruenigen et al33 conducted a prospective observational trial in newly diagnosed endometrial patients preoperatively and 6 months postoperatively. Again, there was a correlation between weight and QOL. Weight, exercise, and fruit and vegetable intake did not change over time; however, CAM use increased significantly at 6 months. Although small, this study highlighted an important observation that may apply to endometrial cancer patients: Without intervention, survivors of endometrial cancer who are sedentary and/or obese are unlikely to spontaneously modify their exercise and nutrition behaviors after diagnosis and treatment.
It is important to implement lifestyle interventions to improve survivorship of endometrial cancer patients who are at increased risk for poor QOL and premature death secondary to obesity-driven comorbidities. A randomized controlled study of an interventional lifestyle program in 45 endometrial cancer survivors demonstrated that patients can lose weight and improve their exercise after the intervention.31 At 12 months, the intervention group lost 3.5 kg, compared to a 1.4-kg gain in the control group, and significantly increased physical activity. Therefore, a lifestyle intervention program in obese endometrial cancer patients is feasible and can result in sustained behavior change and weight loss over a 1-year period. This same research group is presently enrolling more than 100 endometrial cancer survivors to an intervention trial that includes both aerobic exercise and strength training.
QUALITY OF LIFE
QOL is a multidimensional concept that continues to be defined over time. QOL has been defined as an individual’s physical, functional, emotional, and social well-being and how it is impacted by a medical condition and its treatment. QOL measures are reported directly by patients and hence are termed “patient-reported outcomes.” They are not subject to interpretation by either health care providers or research professionals. QOL measurements can provide information about the impact of the disease and its treatment in cancer patients to aid physicians in selecting both antineoplastic and supportive care therapy. A recent meta-analysis of 30 randomized controlled trials from the European Organization for Research and Treatment of Cancer that included survival data for more than 10,000 patients with 11 different cancer sites found that QOL could help to predict survival in patients with cancer.34
There is a paucity of data regarding QOL in early-stage ovarian cancer patients because it is not as common as advanced-stage disease. Traditionally, treatment of ovarian cancer involves removal of both ovaries and the uterus, which puts younger women into menopause and ends their chance of bearing a child. Although women with early-stage ovarian cancer often have an excellent prognosis (5-year survival > 90%), the loss of reproductive potential and lingering psychological survivorship sequelae may result in serious disruptions in QOL. A recent study by Wright et al35 demonstrated that 5-year survival rates for stage I ovarian cancer patients were the same for women who had both ovaries removed and women who had just the cancerous ovary removed, suggesting that ovarian conservation may be considered in select patients.33 This more conservative approach may result in improvements in QOL for women with early-stage disease. Matulonis et al36 studied the QOL of early-stage ovarian cancer patients and observed that even though patients reported good physical QOL scores, one-third of the patients received treatment for family or personal problems, and nearly 60% reported anxiety associated with testing of CA-125.34 Therefore, women with early ovarian cancer clearly benefit from support and interventions for their QOL needs.
Treatment advances for ovarian cancer patients have led to improvements in survival, allowing a broadening of care goals to include maximizing QOL. A single-institution study, in which the majority of ovarian cancer patients had advanced-stage disease, revealed that surgery significantly impacts QOL. QOL markedly decreased after surgery, with a slow improvement during adjuvant chemotherapy, specifically in the physical, functional, and fatigue domains.
Over the past 10 years, several international and GOG randomized trials have included QOL end points for evaluation. The National Cancer Institute of Canada OV10 randomized trial of nearly 700 patients identified that baseline performance status and global QOL were independent predictors of PFS and OS.37 Two large-scale GOG studies (152 and 172) included QOL assessments at several time points in ovarian cancer patients with advanced disease. Wenzel et al compared QOL in patients enrolled in a randomized trial of interval secondary cytoreduction in advanced ovarian carcinoma (GOG 152). The baseline QOL score was positively associated with OS. GOG 172 randomized optimal stage III epithelial ovarian cancer patients to IV paclitaxel plus IP cisplatin and paclitaxel versus IV cisplatin and paclitaxel and found an improved OS in the IP arm.38 Physical and functional well-being and ovarian cancer symptoms were significantly worse in the IP arm during and after treatment. In addition, during treatment, patients on the IP arm experienced more QOL disruption, abdominal discomfort, and neurotoxicity. However, 12 months after treatment, only neurotoxicity remained significantly greater for IP patients. In an ancillary analysis of GOG 152 and GOG 172, patients with lower QOL scores had declines in physical, functional, and emotional well-being. In the physical domain, significant differences were observed in physical symptoms (nausea, pain, feeling ill, and being bothered by the side effects of treatment), as well as more general effects (lack of energy, meeting needs of family, and forced to spend time in bed). These patients were least likely to sleep well. Regarding emotional well-being, there were significant differences in feeling nervous and worrying about dying.
Limited studies have been performed specifically assessing QOL in women with endometrial cancer. Limitations of prior research have included heterogeneous gynecologic populations and different adjuvant therapies, and the studies have not been well controlled. A recent, large study compared QOL among 5- to 10-year survivors of stage I to II endometrial cancer treated with surgery alone or surgery with external beam adjuvant therapy.39 Comorbidity appeared to be the only variable that was negatively associated with all QOL subscales. On multivariate analyses, adjuvant radiation was negatively associated with vitality and physical and social well-being scale scores. Unfortunately, BMI was not a controlled variable. In addition, the current adjuvant treatment for endometrial cancer patients at intermediate risk for recurrence is vaginal radiation not pelvic radiation. In addition, no studies have assessed obesity as the key variable of QOL in endometrial cancer.
QOL is compromised in endometrial cancer survivors, but not for the same reasons as in ovarian cancer patients. A recent ancillary analysis of 2 prospective endometrial cancer QOL trials revealed that scores were similar to normative data in age-matched women without cancer. BMI was inversely correlated with functional, physical, and social well-being and with several decreases in line items within the functional domain, including ability at work and being content. BMI also had an inverse relationship with the “lack of energy” item in the physical domain. Fatigue was present in nearly 30% of survivors, which increased as weight increased.
SUPPORTIVE CARE
Supportive care recognizes that life-threatening illness, whether it can be cured or controlled, carries with it significant burdens of suffering for patients and their families and that this suffering can be effectively addressed by modern palliative care (Table 22-3). Palliative care focuses on management of symptoms, psychosocial support, and assistance with decision making and has the potential to improve quality of care and reduce the use of futile medical services. However, palliative care has traditionally been delivered late in the course of disease. In a recent study of more than 100 patients with metastatic non–small-cell lung cancer, early palliative care led to significant improvements in survival, QOL, and mood.40 As compared with patients receiving standard care, patients receiving early palliative care had less aggressive care at the EOL but longer survival. Researchers conducting a survey at a cancer center found that providers perceived the term “palliative care” as distressing and reducing hope to patients and families. These health care professionals significantly preferred the term “supportive care” over “palliative care” and were more likely to refer patients on active primary and advanced cancer treatments. This renaming has been embraced by other practitioners who also hope it reinforces the concept of an integrated-care model in which receipt of cancer therapies and symptom management are addressed concurrently.
Table 22-3 Goals of Supportive Care Model
Improve quantity of life
Improve quality of life
Minimize disease-specific and treatment-related symptoms
Facilitate open, ongoing conversation with the patient and family regarding shifting treatment focus as appropriate
Utilize consultation and other expertise as needed to meet the above goals
Palliative Care
The term “palliative care” refers to those aspects of medical care concerned with the physical and psychosocial issues faced by a patient with cancer and his or her family. The WHO defines palliative care as an approach that supports and improves the QOL of patients and their families facing the problems associated with a life-threatening illness, such as cancer, through the prevention and treatment of distressing symptoms and attention to psychological and spiritual aspects of patient care. Although all patients with gynecologic cancer may benefit from attention to the physical and psychosocial consequences of a cancer diagnosis, for those with advanced or recurrent disease, this care is imperative. This type of care may be provided while patients are on medical therapy and/or when patients transition off treatment. Palliative care embraces the medical ethics of patient choice and the value of well-being.
Ethical Obligations
Physicians and health care providers have ethical obligations to all patients, and those on palliative care for cancer are no different. However, the provider may be more reflective of their obligations during this stage of a patient’s disease. The ethical principles of autonomy, beneficence, and nonmaleficence have long been accepted as providing a framework for study of moral problems in medicine. Autonomy directs us to respect the choices, values, and life plans of patients and generates the requirements for informed consent. Beneficence forms the fundamental duty to promote patients’ well-being. Nonmaleficence, the duty to refrain from harm, reflected in the Hippocratic Oath, is thought to be the most inflexible of medical ethical principles. Each of these will have different implications for palliative care depending on the sense of the term. Most hospitals have ethical committees that can help the physician or health care provider if there is an ethical dilemma in a patient’s care.
Assessment
There are many options in the clinical delivery of palliative care. The most traditional and frequently used is the medical model of the physician assessing the patient in his/her office and addressing the patient’s needs or directing the patient to other health care providers who can prescribe specific care. Multidisciplinary care has been criticized in the past because of poor communication, cost, and fragmentation of care. However, with the development of electronic medical records, the communication flaw may be rectified. Another medical model is interdisciplinary care, which involves a team of health care professionals including, as needed, the primary physician, a palliative care physician, nurse(s), social worker, physical and occupational therapist, dietician, speech pathologist, pastoral care, pharmacy professionals, bereavement providers, and volunteers. Depending on the hospital, institution, or health system, this model will vary along with collaborators, but among all, the goal is to embrace collaboration and open communications. In addition, as the trajectory of a patient’s disease changes, the patient’s needs and collaborative providers may change. Specific components of a patient’s evaluation will include history of illness, treatment responses, obtaining an understanding of the patient’s decision-making capacity (especially in the elderly), and physical, psychological, social, and spiritual assessments. This type of robust assessment takes time and may require multiple providers.
Discussion of Prognosis
Communication and understanding between the physician, patient, and family are pivotal to supportive cancer care. Physicians inform their patients well regarding cancer treatment; however, they differ in their ability to discuss prognosis and alternatives to anticancer treatments. The majority of cancer patients report a preference for detailed information about their disease, although some prefer to negotiate the extent and timing of the information they receive from oncologists.
Few physicians have received training in the communication skills necessary to discuss palliative care and EOL. It is imperative that physicians start by choosing the appropriate setting to hold these conversations. Physicians do not need to hold these conversations alone; often it is supportive to both patient and physician to have the patient’s family, primary chemotherapy nurse, or social worker in the room. Others can be helpful in reframing or restating terminology for the patient and her family. Physicians need to be aware of the time commitment of such discussions and schedule sufficient time in the office or on hospital rounds. Options for beginning the conversation include starting with a warning phrase, such as “I’m afraid I have bad news.” More than 1 session may be needed, and it can be an ongoing conversation from clinic visit to clinic visit. Physicians should discuss options of care with patients in an honest, sensitive, and straightforward way. They should also be willing to talk about dying and to use the words “death” and “dying.” During the conversation, providers should confirm that patients understand the information being conveyed. As disease progresses, the frame of reference of hope will change. For example, the hope of prolongation of life will change to the hope of a good QOL at the EOL, minimization of symptoms, and opportunity to accomplish whatever activities or goals are important to the patient. If these discussions are not held, patients may seek others who offer false hope with ineffective and potentially harmful therapies.
Decision Making: Role of the Patient, Family, and Physician
Studies of decisions about treatment during palliative care and at the EOL have suggested that there are numerous personal characteristics of physicians, patients, and their families that influence decisions independently of actual prognosis. These include age, sex, education, religion, and personality characteristics. At times, patients and their families report a willingness to continue to seek aggressive therapies even in the face of progressive disease. Although this persistence may reflect the positive effects of maintaining hope, there is also some evidence that treatments thought to be life extending are more likely to be chosen over comfort-oriented treatment plans when patients and even physicians overestimate survival time.
Evaluation of Outcomes
The literature is sparse when assessing outcomes in women receiving palliative care for gynecologic cancer. It is unclear at what point in the course of disease a patient accesses palliative care; however, from the literature, we can deduce that it is quite variable. In addition, most of the research in ovarian cancer patients is directed toward the EOL. A retrospective multi-institutional study of more than 100 patients revealed that ovarian cancer patients have increased hospitalizations and palliative clinical events as they approach the EOL.41 Significant clinical events in the study were defined as ascites, bowel obstruction, and pleural effusion. Many of these patients were treated for palliative intent with paracentesis, thoracentesis, and medical/surgical management of bowel obstructions. In this study, patients who received aggressive care did not have improvement in survival. The authors concluded that short chemotherapeutic remissions and increasing hospitalizations with significant clinical events are indicators to reduce cure-oriented therapies and increase palliative and supportive care.
Symptom Management
Throughout the disease course, aggressive symptom management can improve patients’ QOL and their ability to tolerate and continue to receive treatment.
Pain Management
Pain is a common symptom in cancer patients that can affect both QOL and other symptoms, but it is not always well addressed. The WHO advocates following a “3-step management ladder.” In the setting of pain, there should be prompt oral administration of drugs in the following order: (1) nonopioids (aspirin and acetaminophen); then (2), as necessary, mild opioids (codeine); then (3) strong opioids such as morphine, until the patient is free of pain. To maintain freedom from pain, drugs should be given on a schedule such as every 2 to 6 hours rather than when requested or “on demand.” Adjuvant analgesics are also commonly used and are defined as medications with a primary indication other than pain that have analgesic properties in some painful conditions. The group includes numerous drugs in diverse classes. Some adjuvant analgesics are useful in several painful conditions and are described as multipurpose adjuvant analgesics (eg, antidepressants, corticosteroids, α2-adrenergic agonists, neuroleptics), whereas others are specific for neuropathic pain (eg, anticonvulsants, local anesthetics, N-methyl-D-aspartate receptor antagonists), bone pain (eg, calcitonin, bisphosphonates, radiopharmaceuticals), musculoskeletal pain (eg, muscle relaxants), or pain from bowel obstruction (eg, octreotide, anticholinergics). In a multisite, randomized clinical trial, nearly 400 patients with advanced cancer who were experiencing moderate to severe pain received 6 30-minute massage or simple-touch sessions over 2 weeks.42 Although both groups demonstrated immediate improvement in pain and mood, massage led to larger improvements in both.
Nausea and Vomiting
Nausea and vomiting in the gynecologic oncology patient may be disease- or treatment-related. Nausea arising from stimuli in the gastrointestinal tract associated with slowing of the gut should respond to gastrokinetic antiemetics, such as metoclopramide, that promote gastric emptying and increase gut motility. However, bowel obstruction must be considered in patients with intra-abdominal disease; in these patients, stimulating agents may worsen symptoms.
Chemotherapy-induced nausea and vomiting (CINV) occurs based on the intrinsic emetogenicity of a given chemotherapeutic agent and the age and sex of the patient and may occur in 70% to 80% of patients receiving chemotherapy (Table 22-4).43 A number of chemotherapy regimens for gynecologic oncology patients include medications with high (cisplatin) and moderate (carboplatin, cyclophosphamide, doxorubicin, ifosfamide) risk of emesis. CINV can be divided into 4 subcategories: acute, delayed, anticipatory, and breakthrough CINV. The National Comprehensive Cancer Network (NCCN) defines acute nausea as that occurring shortly after chemotherapy administration but resolving within 24 hours. Delayed nausea occurs after 24 hours, peaks between 48 and 72 hours, and resolves by the day 6 or 7. Anticipatory nausea is described as a learned or conditioned response prior to chemotherapy. Finally, breakthrough CINV can occur when a patient experiences symptoms despite appropriate treatment.
Table 22-4 Chemotherapy-Induced Nausea and Vomiting (CINV)
Types of CINV
Acute, delayed, anticipatory, breakthrough
First-line therapy
5-Hydroxytryptophan, serotonin receptor antagonists, corticosteroids, aprepitant, a neurokinin-1 receptor antagonist
Second-line or adjuvant options
Prokinetic agents (metoclopramide and ginger), phenothiazines, butyrophenones, cannabinoids, benzodiazepines, acupuncture, vitamin B6
First-line therapy of CINV consists of agents with high therapeutic index that are chosen based on a regimen’s emetogenic potential and incidence of delayed emesis and includes 3 main classes of drugs: 5-hydroxytryptophan (5-HT3) serotonin receptor antagonists, corticosteroids, and aprepitant, a neurokinin-1 receptor antagonist. For breakthrough CINV, agents with a lower therapeutic index (eg, metoclopramide, phenothiazines, butyrophenones, cannabinoids) may be considered when first-line therapeutics fail. Ideally, anticipatory CINV is prevented by avoiding or minimizing acute and delayed emesis. When anticipatory CINV does occur, benzodiazepines and behavioral therapy are suggested. A recent Cochrane review of the literature supports the efficacy of acupuncture point stimulation for acute CINV as well as for postoperative nausea.44 In a randomized study of ovarian cancer patients, all of whom were receiving a standard antiemetic regimen, the combination of vitamin B6 and acupuncture led to significantly fewer emesis episodes and a greater proportion of emesis-free days when compared with acupuncture or vitamin B6 alone. In a randomized, double-blinded crossover study in nearly 50 gynecologic cancer patients receiving cisplatin-based chemotherapy, ginger in capsule form was found to be equivalent to metoclopramide for delayed nausea.
Gastrointestinal Symptoms
Gastrointestinal (GI) symptoms that physicians will encounter include nausea and vomiting (discussed in the previous section), constipation, GI hypomotility progressing to bowel obstruction, oral and intestinal mucositis, and ascites. GI symptoms are common in patients with ovarian cancer even in early stages prior to diagnosis.
GI Hypomotility
Constipation in the gynecologic oncology patient may be disease related or may be an adverse effect of medications including narcotics or selective 5-HT3 antagonists. Perioperative and medication-related constipation can be avoided though anticipation, hydration, and the use of laxatives. Stool softeners, peristaltic agents, and osmotic laxatives may be used. Bulking agents may not be appropriate in patients who are not able to hydrate, have radiation-related dysfunction, or have extensive intra-abdominal disease. Women with extensive intra-abdominal disease with involvement of the mesenteric plexus may present with GI hypomotility, and treatment is aimed at increasing bowel peristalsis with medications such as metoclopramide and avoidance of constipation and impaction with hydration and appropriate laxatives.
Bowel Obstruction
Bowel obstruction in gynecologic malignancy is a complex issue in the setting of recurrent disease, and given the heterogeneity of patients and their clinical courses, literature to date offers limited guidance.45 Many ovarian cancer patients will experience a bowel obstruction and, with their physicians, will have to make decisions regarding therapeutic options (surgical, medical, or supportive). Management decisions should be based on the patient’s prognosis, performance status, and current goals of care. For patients focusing on managing discomfort, a combination of methods can be used, including pain management, antiemetics, corticosteroids, percutaneous gastrostomy placed endoscopically or by interventional radiology, and medications for decreasing intestinal secretions. Octreotide for this purpose has been shown to control emesis and to improve QOL and decrease hospitalization.
In 2010, Cochrane reviewers examined the literature and found only low-quality evidence comparing palliative surgery and medical management for bowel obstruction in ovarian cancer identifying only 1 study that met their inclusion criteria. They were unable to reach definite conclusions about the relative benefits and harms of the 2 forms of treatment or to identify subgroups of women who are likely to benefit from one treatment or the other.45 In the only study that met the Cochrane reviewer’s inclusion criteria, Mangili et al46 analyzed retrospective data for 47 women who received either palliative surgery or medical management with octreotide and reported OS and perioperative mortality and morbidity. Although 6 surgical patients (22%) had serious complications of the operation and 3 patients (11%) died of complications, multivariable analysis found that women who received surgery had significantly better survival than women who received octreotide. However, the patients were not randomized, and women in the surgery group had significantly better performance status. Researchers recently reported on a small highly selected group of patients with ovarian cancer undergoing palliative endoscopic or operative procedures whose symptoms they followed prospectively. They noted symptomatic improvement or resolution within 30 days in 23 (88%) of 26 patients, with 1 (4%) postprocedure mortality. At 60 days, 10 (71%) of 14 patients who underwent operative procedures and 6 (50%) of 12 patients who had endoscopic procedures had symptom control. Median survival from the time of the palliative procedure was 191 days for those undergoing an operative procedure and 78 days for those undergoing an endoscopic procedure.
For large bowel obstruction, less invasive strategies like colonic stenting can help patients with recurrent malignant disease, although limited data on their use are available for gynecologic oncology patients. A recent study by Caceres et al47 demonstrates the feasibility of this strategy in acutely ill gynecologic cancer patients who had successful stent placement.
Oral and Intestinal Mucositis
Oral and intestinal mucositis in the gynecologic oncology patient can be related to chemotherapy, radiation, or disease and can present with oral and esophageal ulceration, diarrhea, and tenesmus. Pathophysiology remains unclear, although recent work suggests that disturbances in bacterial microflora may contribute. Cochrane reviewers evaluated a wide range of preventive interventions for oral mucositis and found that compared with a placebo or no treatment, the following treatments showed benefit: amifostine, TCM, hydro-lytic enzymes, and ice chips.48 Other interventions showing some benefit with only 1 study were benzydamine, calcium phosphate, etoposide bolus, honey, iseganan, oral care, and zinc sulphate. In addition, L-glutamine has shown promise as a preventive and therapeutic agent for treatment-related mucositis. Palifermin, a human keratinocyte growth factor, reduced the duration and severity of oral mucositis after intensive chemotherapy and radiotherapy for hematologic cancers. In a review of 32 treatment trials for oral mucositis involving 1500 patients, no benefits were seen with benzydamine HCl versus placebo or sucralfate versus placebo. Only low-level laser showed a reduction in severe mucositis when compared with a sham procedure. Opioid pain management has also been shown to be effective for mucositis-related pain.49 A gynecologic cancer–specific study evaluated the impact of circadian rhythms on radiation-related mucositis manifesting as diarrhea in cervical cancer patients. More than 200 patients with cervical carcinoma were randomized to morning and evening arms. Although radiation response rates were similar, overall (grades 1-4) and higher-grade (grades 3 and 4) diarrhea was found to be significantly increased in the morning arm compared with the evening arm.
Gynecologic cancer patients with diarrhea and tenesmus also need to be evaluated for disease progression. Loperamide may be beneficial in the setting of radiation- or chemotherapy-induced diarrhea when disease progression and Clostridium difficile infection have been excluded. Tenesmus usually responds to anticholinergic agents, corticosteroids, and opioids, often in combination. In severe cases of radiation enteritis and proctitis, surgical intervention may be required.
Ascites
Ascites is a frequent issue in ovarian cancer patients, and the approach to symptom management will depend on the patient’s current goals of care. Diuretics, intermittent IP paracentesis, permanent indwelling catheter, and sparing diuretics may be used. Malignant ascites often has a profound impact on the QOL of patients with refractory and heavily treated ovarian cancer. In retrospective studies, indwelling IP catheters appear to be a safe and effective palliative strategy to manage refractory malignant ascites, without overwhelming infection rates.50 Some practitioners use IP cisplatin with success in highly selected patients to palliate symptomatic ascites. New biologic therapeutics may be a future option of treatment. Laboratory research demonstrates that a high content of vascular endothelial growth factor in ascites might be responsible for increased peritoneal permeability, resulting in the production of ascites. Case reports have studied the successful use of bevacizumab in palliative treatment of ascites in ovarian cancer patients. Toxicity was manageable, and no therapeutic paracenteses were required after initiation of therapy. Further prospective trials should consider evaluation of these agents as a tool for palliation treatment of ascites during the EOL.
Respiratory Symptoms
Respiratory symptoms in gynecologic oncology patients may be related to pulmonary tumor burden from lung metastasis or from pleural effusion. In addition, cancer-related cachexia, malnutrition, fatigue, anemia, and metabolic acidosis may contribute to dyspnea. In the setting of pleural effusion, decisions regarding interventions should be made based on patient prognosis and goals of care. Interventions such as thoracentesis, placement of indwelling catheter, and chemical pleurodesis may be considered. The American Thoracic Society consensus statement defines dyspnea as “a subjective experience of breathing discomfort that consists of qualitatively distinct sensations that vary in intensity,” not necessarily related to hypercapnia or hypoxia.51 A systematic review of the evidence for the efficiency of pharmacologic and nonpharmacologic treatments in alleviating dyspnea in terminal cancer patients revealed a paucity of randomized controlled trials on interventions for alleviation of dyspnea. Their review supported the use of opioids for dyspnea relief in cancer patients, but the use of supplemental oxygen to alleviate dyspnea was recommended only in patients with hypoxemia. A review of pharmacologic approaches to dyspnea confirmed benefits of systemic opioids, administered orally or parenterally. In addition, authors found that oral promethazine may also be used as a second-line treatment. Nursing-led nonpharmacologic interventions such as counseling, relaxation, and teaching coping strategies seemed to provide benefit although studies were limited.
Urinary Tract Symptoms
Urinary tract symptoms in the gynecologic oncology patient may be disease- or treatment-related. Women with both early- and late-stage ovarian cancer may present with symptoms of urinary urgency and frequency. Cervical cancer patients may have ureteral obstruction and bladder involvement by tumor; in addition, treatment-related symptoms include bladder dysfunction after radical hysterectomy, radiation cystitis, and ureterovaginal or vesicovaginal fistulas. Ureteral obstruction, with subsequent infection, pain, and acute renal failure (in the setting of bilateral obstruction), may justify mechanical measures such as nephrostomy or ureteric stent insertion in selected cases. When prognosis is otherwise limited, these invasive procedures may introduce unnecessary morbidity. Bladder dysfunction may be associated with radical hysterectomy, and some authors have advocated nerve-sparing approaches to decrease incidence. Radiation for cervical and endometrial cancer can cause urinary tract symptoms including immediate effects (bladder irritation or cystitis) and late effects (hematuria, fibrosis and contraction, or fistulas). In cervical cancer, the 10-year bladder complication rate in a series from the MD Anderson Cancer Center was 3%. On multivariate analysis, a central pelvic dose of external beam radiation > 50 Gy, black race, smoking, and obesity were significantly associated with increased risk of bladder complications. Bladder symptoms may be treated with nonsteroidal anti-inflammatory medications for detrusor irritability or drugs with an anticholinergic action to reduce bladder contractility. Infection should also be assessed. Fistulas are ideally treated with surgical diversion; however, in settings of limited prognosis, urinary catheterization may ameliorate symptoms.
Edema
Thromboembolic disease, lymphedema, and severe nutritional deficiency can contribute to acute and chronic edema in the gynecologic oncology patient. In addition, recurrent or progressive tumor may contribute to edema. Cancer diagnosis, advanced age, abdomino-pelvic surgery, obstructing lesions, and treatment with thrombogenic chemotherapy regimens all put gynecologic oncology patients at high risk for venous thromboembolism (VTE). The reported rate of VTE in gynecologic cancer patients ranges from 11% to 18%, with the rate of pulmonary embolism (PE) between 1% and 2.6%. Among postoperative ovarian cancer patients, the rate of PE is as high as 7%. Perioperative prevention is essential, and the authors support a regimen similar to those advocated in the literature of dual prophylaxis with sequential compression devices plus heparin every 8 hours or daily low molecular weight heparin with extended prophylaxis for 2 to 4 weeks after surgery for high-risk patients. For the patient who has been diagnosed with a VTE, prolonged use of a low molecular weight heparin over oral anticoagulants to decrease VTE recurrence is supported by a current Cochrane review.52
A population-based study in Australia found that 10% of gynecologic cancer survivors who responded to a survey reported being diagnosed with lymph-edema, and a further 15% reported undiagnosed “symptomatic” lower limb swelling.51 The highest prevalence (36%) of diagnosed lymphedema was found in vulvar cancer survivors. For cervical cancer survivors, radiation and lymphadenectomy conferred increased risk of developing swelling. For uterine and ovarian cancer survivors, those who had lymph nodes removed or who were overweight or obese had the greatest chance of developing swelling. Treatment for lymph-edema in the gynecologic oncology patient has been poorly studied, and most experience has been gained from breast cancer patients. Complete decongestive therapy for lymphedema consists of an acute treatment phase and a lifelong maintenance phase and combines manual lymph drainage, compression bandaging, and therapeutic exercise. Skin and nail care with inspection for cuts, scratches, irritation, or infection is also essential given risk of cellulitis. In the gynecologic patient with a limited life span, nutritional deficiency, hypoalbuminemia, immobility, and progressive obstructive tumor may all contribute to edema.
Fatigue
Cancer-related fatigue (CRF) is a prevalent and disabling symptom experienced by both cancer patients and cancer survivors. CRF is a multifaceted condition characterized by diminished energy and an increased need to rest, disproportionate to any recent change in activity level. It is accompanied by other clinical characteristics, including generalized weakness, diminished mental concentration, insomnia or hypersomnia, and emotional reactivity. Decrements in physical, social, cognitive, and vocational functioning; adverse mood changes; sleep disturbances; treatment non-compliance; and emotional and spiritual distress for both patients and their family members are among the consequences of CRF. The etiology and risk factors for CRF are multifactorial, and in an excellent recent review, Mitchell describes potentially contributing factors, including direct treatment-related effects, cancer-related conditions, and the adverse effects of medications.53 Specific etiologies that are implicated include anemia; myeloid suppression; mood disorder; concurrent symptoms such as pain or sleep disturbances; electrolyte disturbances; cardiopulmonary, hepatic, or renal dysfunction; hypothyroidism; hypogonadism; adrenal insufficiency; infection; malnutrition; deconditioning; and skeletal muscle atrophy/weakness. Evidence-based guidelines from the NCCN recommend a symptom-oriented and individualized approach to each patient. A combination of exercise, psychoeducational interventions, efforts to manage concurrent symptoms, interventions to improve sleep quality, judicious use of medications such as modafinil and methylphenidate, and complementary therapies such as relaxation, massage, healing touch, and acupuncture is thought to offer the greatest likelihood of success.49
There are limited studies specific to fatigue in the gynecologic oncology population. Thirty-two women treated for recurrent gynecologic cancer and fatigue were prescribed methylphenidate at morning and noon over an 8-week period. Patients reported significant declines in fatigue and improvement in both mood and QOL at the end of the study when compared with baseline scores.54 Forty-three women with gynecologic cancer receiving platinum chemotherapy were followed longitudinally in a trial of warm water footbath for CRF. Participants in the experimental group reported a significant reduction in fatigue and improvement in sleep quality from the second session of chemotherapy and continued to improve during the 6-month study period. Fifty-one women with ovarian cancer (n = 37) or breast cancer (n = 14) participated in 10 weekly 75-minute restorative yoga classes that combined physical postures, breathing, and deep relaxation. Significant improvements were seen for depression, negative effect, state anxiety, mental health, and overall QOL. QOL improved and fatigue decreased between baseline and follow-up.55
Peripheral Neuropathy
Like other cancer-related symptoms, neuropathy can be due to both cancer and cancer treatment. In gynecologic malignancies, involvement of the sacral plexus by tumor can produce significant neuropathic pain. In addition, radiation treatment for endometrial and cervical cancer can lead to neuropathy when the sacral plexus is in the treatment field. Many agents cause chemotherapy-induced peripheral neuropathy (CIPN); the most common causes in the gynecologic oncology population are cisplatin, carboplatin, paclitaxel, and docetaxel. The functional effects of CIPN can significantly reduce a patient’s QOL by introducing limitations such as not being able to hold a baby safely, button a shirt, or type on a keyboard. Pain, paresthesia (numbness), and reduced proprioception can all occur; symptoms may be constant or intermittent and vary in severity. The pain may be characterized as tingling, cold, burning, or dull.
In patients receiving treatments that put them at risk for CIPN, prevention, treatment, and maintaining functionality and safety should all be considered. Preventive agents still in the preclinical phase of study include acetyl-L-carnitine, α-lipoic acid, and ethosuximide, a selective antagonist of calcium channels. Clinical trials of preventive agents have been limited by small sample sizes, inconsistent methods for assessment, lack of randomization, and/or inclusion of multiple chemotherapeutic agents with potential neurotoxic effects. Several trials of glutathione in ovarian cancer patients receiving cisplatin have shown neuroprotective effects. Randomized clinical trials have shown protective effects of vitamin E supplementation in patients receiving cisplatin or cisplatin-paclitaxel combinations.56 Oral glutamine, an amino acid that induces the transcription of nerve growth factor mRNA, was evaluated in a randomized controlled trial and found to significantly reduced incidence and severity of oxaliplatin-related peripheral neuropathy without a reduction in the efficacy of chemotherapy. Treatment of CIPN includes the use of opioids and adjuvant analgesics. Opioids have demonstrated efficacy for relieving various types of neuropathic pain in randomized controlled studies. Adjuvant analgesics used for CIPN include corticosteroids, anticonvulsant agents, tricyclic antidepressants, local anesthetics, and anticancer therapies. Corticosteroids have efficacy in reducing neuropathic pain; however, their side effect profile limits their use in patients with prolonged survival. Although anticonvulsant agents have been used with significant benefit for CIPN, anecdotally and in case reports, randomized controlled trials do not support their use. Tricyclic antidepressants may have efficacy for neuropathic pain, but their anticholinergic and histaminergic side effects may limit use. Of note, a randomized, double-blind, phase 2 trial of nortriptyline failed to show a significant benefit. Local anesthetics have demonstrated efficacy for several neuropathic pain syndromes, including diabetic neuropathy. Finally, acupuncture has shown improvement in nerve conduction studies in peripheral neuropathy and showed promising results in a case series of CIPN.57
Safety precautions are important for women suffering from neuropathy. Patients should be aware that water temperature might be hotter than they sense when they are bathing or washing dishes. Clearing hallways and stairwells and making sure they are well lit may also be important when proprioception is affected. In addition use of nonskid mats in bathtubs and wide-based soles may be beneficial.
Hypercalcemia
Hypercalcemia of malignancy occurs in 10% to 30% of patients with cancer, and etiologies include humoral hypercalcemia of malignancy (HHM), which may or may not be mediated by the paraneoplastic secretion of parathyroid hormone–related peptide (PTHrP), and local osteolytic hypercalcemia in the setting of bone metastasis. In gynecologic cancer, hypercalcemia has been reported with ovarian small-cell carcinoma, papillary serous carcinoma, clear cell carcinoma, and dysgerminoma, as well as with uterine leiomyosarcoma and endometrial, cervical, and vulvar carcinoma. A review of more than 5000 gynecologic cancer patients identified 256 patients with hypercalcemia (5%).58 Most patients (82%) had mild hypercalcemia. Severity of hypercalcemia was associated with disease stage, use of hyper-calcemia treatment, and survival duration. A review of the published cases in the gynecologic oncology literature identified 34 patients with HHM that was PTHrP mediated, of whom 22 had ovarian cancer, 6 had uterine cancer, 3 had vulvar cancer, and 3 had cervical cancer. Clear cell carcinoma was the predominant histology.
Although mild hypercalcemia may be asymptomatic, moderate to severe hypercalcemia can be associated with life-threatening neurologic, cardiac, GI, and renal signs. The treatment of hypercalcemia depends on the level, chronicity, and origin of the condition. General measures used in the treatment of moderate to severe hypercalcemia in patients with cancer include aggressive volume replacement with saline diuresis and inhibitors of bone resorption such as the bisphosphonates. Additional treatments include glucocorticoids and oral phosphate. Response to hypocalcemic treatment is gauged by resolution of symptoms and decrease in serum calcium concentrations.
End-of-Life Care
QOL During Palliative Care
QOL during palliative care is particularly challenging as physicians confront the crucial decision of whether to prescribe therapies that may be futile in prolonging life. However, palliative therapy can be justified when the goal is to improve QOL and specific symptoms. Cancer patients frequently receive chemotherapy near the EOL, and the literature suggests no association between aggressiveness of care and OS. The role of chemotherapy at the EOL was questioned in a pilot study of advanced recurrent ovarian cancer patients in which patients believed that psychosocial issues play a greater role in determining their QOL than their physical QOL. A retrospective study of more than 100 deceased ovarian cancer patients showed that patients with a shorter survival time had a trend toward increased chemotherapy during their last 3 months of life and had increased overall aggressiveness of care. Short disease remissions and clinical events such as frequent hospitalizations and procedures for pleural effusions and ascites were indicators for reducing cure-oriented therapies and increasing palliative interventions.41 A prospective observational trial, GOG-QLM0301 is being developed by the GOG to study QOL and care needs in patients with platinum-resistant ovarian, fallopian tube, or peritoneal cancer.
Goals of Care at EOL
As with palliative care, the purpose of assistance at the EOL is to relieve any type of suffering. The obligation of the physician to serve is particularly focused when death is eminent. Spirituality is an important aspect of palliative care at the EOL. If the physician is not comfortable addressing these issues, then the appropriate services, such as pastoral care, must be involved. Bereavement care should also be accessed during palliative care but before the immediate EOL. Hospice services, whether inpatient or at home, can help the physician facilitate this transition. The goal of hospice is to provide compassionate, holistic care for patients and their families and to maximize patients’ QOL at the EOL.
Site of Care
The majority of gynecologic cancer patients prefer EOL care at home. Brown et al59 performed a survey and asked the patients to envision being informed by their physicians that efforts to cure or control the spread of their disease were failing. Fifty-seven percent of the gynecologic cancer patients, regardless of disease status, preferred to be treated at home. However, patients’ preferences do not always translate into reality. In a multi-institutional retrospective analysis, von Gruenigen et al39 revealed that 46% of ovarian cancer patients died at home, 21% died in hospice, and 17% died in a hospital. A study of gynecologic oncology patients in Toronto found that 51% of ovarian cancer patients, 49% of uterine cancer patients, and 53% of cervical cancer patients died in an acute care bed.60 Therefore, it is imperative that the physician and the health care team have transparent communication with patients about their preferences and needs.
As health care providers for women with gynecologic malignancies, we can simultaneously maximize survival and QOL for our patients. We have a wide range of continuously evolving tools at our disposal, including conventional therapies, lifestyle modification, integrative modalities, and supportive care. Appropriate use of these therapies throughout the life cycle can enable us to support the innate healing abilities of our patients and help them achieve their life goals.
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