Nonpharmacologic Complementary Therapies in Symptom Management for Breast Cancer Survivors

Nonpharmacologic Complementary Therapies in Symptom Management for Breast Cancer Survivors Anne H. Blaes,a Mary Jo Kreitzer,b Carolyn Torkelson,c and Tufia Haddada The request and use of nonpharmacologic interventions and complementary and alternative medicine (CAM) in cancer survivors is increasing. Given the large number of breast cancer survivors and the multiple treatment-related symptoms they endure, it is important for physicians to be aware of the evidence supporting nonpharmacologic therapies. Several studies evaluating such interventions have demonstrated improved overall quality of life (QOL). For other symptoms, the literature is limited but growing. We summarize the evidence to support complementary and alternative therapies for the major symptoms in breast cancer survivors. Semin Oncol 38:394-402 © 2011 Elsevier Inc. All rights reserved.

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n 2005, the Institute of Medicine stated there were more than 10 million cancer survivors with roughly one in 30 being a breast cancer survivor. For breast cancer, between 1996 and 2006, the US incidence increased 19% and the breast cancer–specific mortality decreased 24%.1 As a result, the number of breast cancer survivors is increasing, and represents more than 40% of all female cancer survivors.2 Many breast cancer survivors endure a multitude of symptoms after treatment. These symptoms and late effects from therapy may include fatigue, hot flashes, insomnia, musculoskeletal disturbances, neurocognitive changes, neuropathy, weight gain, sexual dysfunction, and anxiety and depression (Table 1). In the Women’s Healthy Eating and Living Study, breast cancer survivors treated between 1995 and 2000 completed a survey about complementary and alternative medicines (CAM) to improve symptom and quality of life (QOL) measures. Of 2,527 individuals, 2,017 (80%) reported use of CAM.3 The highest disclosure rates were for naturopathy (85%), homeopathy (74%), acuaDepartment

of Medicine, Division of Hematology/Oncology/Transplantation, University of Minnesota, Minneapolis, MN. bCenter for Spirituality and Healing, University of Minnesota, Minneapolis, MN. cDepartment of Family Medicine and Community Health, University of Minnesota, Minneapolis, MN. Financial disclosures: none. Address correspondence to Tufia Haddad, MD, University of Minnesota, 420 Delaware St, SE, MMC 480, Minneapolis, MN 55455. E-mail: [email protected] 0270-9295/ - see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1053/j.seminoncol.2011.03.009

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puncture (71%). and chiropractic medicine (47%). In another study in 1,904 cancer survivors, 40% reported using CAM within the prior year. Of the CAM therapies, 64% used prayer for healing. Compared to the general population, cancer survivors were 36% more likely to have used CAM. These results were confirmed in both recent and long term (⬎10 years) cancer survivors.4 Often, cancer survivors do not disclose this information to their physicians.3,5–7 With the high use of CAM therapies, there is a need to better understand what CAM therapies are available, and the evidence to support their use. Dietary modifications and physical activity are key components in the overall health of breast cancer survivors. This report summarizes the evidence to support CAM therapies for the major symptoms, including hot flashes, fatigue, arthralgias, neuropathy, insomnia, cognitive deficits, and QOL (Table 2).

HOT FLASHES Hot flashes are extremely common and can cause significant physical and emotional distress. There are several reasons for the high frequency.8 Most women diagnosed with breast cancer are postmenopausal and some abruptly discontinue hormone replacement therapy at diagnosis. Chemotherapy-induced ovarian dysfunction and therapeutic ovarian suppression or oophorectomy may induce premature menopause. These vasomotor symptoms are also common side effects of endocrine therapy with tamoxifen or an aromatase inhibitor (AI). The frequency and intensity of hot flashes is greater than those experienced by healthy women during spontaneous menopause, and contribSeminars in Oncology, Vol 38, No 3, June 2011, pp 394-402

Complementary therapies for breast cancer survivors

Table 1. Symptoms and Late Effects of Cancer

Therapy in Breast Cancer Survivors Fatigue Hot flashes Insomnia Neuropathy Sexual dysfunction Musculoskeletal disturbances Neurocognitive changes Weight gain Anxiety and depression

ute to lower QOL scores, increased insomnia, and fatigue.9 –11 Two thirds of all breast cancer survivors report hot flashes, and of these, 60% describe symptoms as moderate or extremely severe.12 Successful management is crucial for symptom control and potentially for compliance with adjuvant hormonal therapy.

Placebo Effect A randomized, placebo-controlled trial (RCT) is necessary to demonstrate the efficacy of intervention. Several RCTs with pharmacologic interventions have been conducted, and a meta-analysis determined that on average 37% of women on placebo reported a 50% reduction in their hot flash scores.13 Most RCTs confirm a 20% to 30% reduction in hot flashes frequency and scores within 4 weeks of placebo therapy.14 Several prescription agents consistently demonstrated superiority over placebo, including venlafaxine, gabapentin, clonidine, and several selective serotonin release inhibitors.15–19 These drugs have their own side effects and financial burden, and many women prefer nonprescription interventions.

Vitamins and Supplements At least four separate RCTs have evaluated different soy products and phytoestrogens.20 –23 The products contained varying doses of isoflavones or isoflavonoids. There were no significant differences in hot flashes and menopausal symptom scores compared with placebo. Similar negative results were observed in two separate RCTs with black cohosh, a popular plant-derived product.24 In a recent meta-analysis of black cohosh for menopausal symptoms in women without breast cancer,25 seven of the nine RCTs included demonstrated significant improvement in symptoms. Compared with the general population, hot flashes in breast cancer survivors are more frequent and severe, and this may explain the lack of benefit by black cohosh in these women. Data for nonpharmacologic management of hot

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flashes is largely from single-arm, pilot studies. Vitamin E (800 IU/d) was evaluated by a RCT, compared to placebo, and no significant clinical benefit was found.26 A single RCT of homeopathy also demonstrated no reduction in hot flashes.27

Acupuncture RCTs of true acupuncture (TA) and placebo or sham acupuncture (SA)28 in breast cancer survivors with hot flashes provided mixed results, comparable to the outcomes observed in hot flashes from natural menopause. In one RCT, subjects with baseline three or more hot flashes per day received twice-weekly acupuncture for 4 weeks. When compared with SA, the reduction in hot flashes from TA was not statistically significant.29 A potential limitation is that the SA needles were inserted within a few centimeters of the same sites used in the TA arm, and may have resulted in some therapeutic effect in the SA subjects. An additional randomized pilot study of 10 sessions of acupuncture treatment over 7 weeks reported that TA was not associated with a significant reduction in hot flashes frequency, but it did improve other menopausal symptoms and overall QOL.30 A positive RCT of acupuncture in postmenopausal women taking tamoxifen for early-stage breast cancer also has been reported. Subjects received twiceweekly TA or SA sessions for 5 weeks followed by once-weekly therapy for another 5 weeks. As compared with SA, TA experienced a reduction in both daytime and evening hot flashes, and a less profound but still statistically significant decline in hot flashes that persisted for 12 weeks following the intervention.31

Behavioral Intervention While it is difficult to interpret the data in behavioral intervention trials given the limited number of studies in breast cancer and the lack of placebo arms, some encouraging results have been reported. Breast cancer survivors trained in self-hypnosis over five weekly sessions reported a 68% reduction in hot flashes, and these results were significant compared with a control group (no intervention).32 The hypnosis intervention also significantly improved hot flash–related daily interference scores, sleep quality, and anxiety and depression scores. A comprehensive menopausal assessment (CMA) program focused on hot flashes, vaginal dryness, and stress urinary incontinence symptoms through structured education, counseling, pharmacologic, and behavioral interventions.33 Those in the intervention arm had an individualized care plan, whereas the control group received education and counseling alone. The intervention group had less menopausal symptoms and improved sexual function; however, it is unclear which specific intervention(s) led to these improvements.

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Miscellaneous Pilot data from additional single-arm studies evaluating stellate ganglion block,34,35 magnesium oxide,36,37 and paced breathing38 generated interest, but RCTs will be necessary.

FATIGUE Cancer-related fatigue (CRF)39 affects 30% to 40% of cancer survivors. This fatigue can lead to impaired QOL, and also has been associated with survivors obtaining or maintaining disability benefits.40,41 Some potentially reversible factors include insomnia, anemia, pain, deconditioning, medications, nutritional deficiencies, and emotional distress (adapted from NCCN guidelines: http://www.nccn.org/professionals/physician_gls/ PDF/fatigue.pdf). No gold standard exists40 for nonpharmacologic interventions to treat CRF. Some prescription and overthe-counter agents (methylphenidate, fish oil, coenzyme Q10, guarana, and melatonin) are being studied, but little data exist to support their routine use. Studies of behavioral interventions like relaxation and imagery are limited. Results indicate behavioral therapy produces a nonsignificant effect on fatigue.

Physical Exercise Meta-analyses were performed evaluating the benefit of exercise.42,43,44 Exercise was more beneficial than the control (standard of care) in reducing CRF. While the type of physical activity varied, walking programs, cardiovascular, and/or flexibility training and resistance training had moderate effects for reducing CRF. A systematic review of 14 studies on the effects of exercise programs in breast cancer patients44 showed exercise was associated with improvement in QOL and reduction in fatigue.

Acupuncture Acupuncture has been studied in a limited fashion. In a RCT of 47 cancer survivors not on active therapy, approximately one third were breast cancer patients.45 They were randomized to three arms: acupuncture, acupressure, or sham acupressure. At the end of the 6-week intervention, there was a 36% improvement in fatigue in the acupuncture group, while the acupressure group improved by 19% and the sham acupressure by 0.6%. This pilot study suggested that acupuncture was feasible and may improve CRF.

ARTHRALGIAS Improvements in adjuvant hormonal therapy have contributed to declining mortality rates in estrogen receptor (ER)-positive breast cancer. In postmenopausal women, adjuvant therapy with aromatase inhib-

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itors (AIs) is more effective than tamoxifen in prevention of recurrence. The AIs block peripheral conversion of androgens into estrogen, and in postmenopausal women they induce estrogen deprivation. The side effects reflect this, and include hot flashes, vaginal dryness, sexual dysfunction, accelerated loss of bone density, and musculoskeletal symptoms, most notably, arthralgias. Arthralgias encompass pain and stiffness in the joints not related to inflammatory or degenerative arthritis. The reported incidence of AI-induced arthralgias in the original adjuvant therapy trials is 5% to 35%.46,47 The range in frequency is related to how adverse events were defined and reported. More contemporary observations suggest the rate to be as high as 47%.48 This side effect and its potential to cause noncompliance with therapy are increasingly recognized.

NUTRITION AND SUPPLEMENTS Acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), narcotics, and other analgesics may be used, but they do not impact whether patients maintain initial AI therapy.49 Glucosamine and/or chondroitin sulfate have not been studied, but they have demonstrated benefit in osteoarthritis.50,51

Nutritional Interventions Dietary sources of omega 3 fatty acids, including fish and certain plant/nut oils, may benefit arthralgias. A meta-analysis of RCTs in chronic rheumatoid arthritis reports improvements in morning stiffness and joint tenderness in those who have 3 months of regular intake of fish oil supplements.52,53 Because AI-induced arthralgias are not inflammatory-mediated, placebocontrolled trials with these supplements will be necessary. Another area of current investigation is the impact of regular exercise on AI-induced arthralgias.54

ACUPUNCTURE To date, acupuncture is the only intervention tested against placebo (SA) and demonstrated benefit.55 In one study,55 43 patients were randomized to receive traditional Chinese medicine acupuncture (TA) or SA. Biweekly treatments were administered over 6 weeks. Validated survey tools analyzed joint pain, stiffness, and functional capacity in the hands and knees, as well as general assessments in these domains, at baseline, 3 weeks, and 6 weeks. Baseline characteristics were equivalent in both groups and median age of the subjects was 56 years. Pain scores were reduced by 50% at 6 weeks in the TA arm, whereas there was no improvement with SA. No adverse events were reported. Of those receiving TA, 74% said they would continue acupuncture following study participation, and 59% were willing to pay for this service.

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NEUROPATHY

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on chemotherapy-induced peripheral neuropathy. One study (N ⫽ 27) reported grade 1 improvement in the peripheral neuropathy scale in 73% of participants,80 while another that 23 of 25 patients had significantly improved total neuropathy scale scores 8 weeks after administration.81

Treatment of breast cancer most often includes adjuvant combination chemotherapy. Taxanes (paclitaxel or docetaxel) are frequently included. Neurotoxicity is one of the major side effects of taxanes that may result in a dose reduction or even premature chemotherapy termination. While the incidence of chemotherapy-induced neurotoxicity has been reported to be as high as 60%, peripheral neuropathy typically occurs in 10% to 20% of cancer patients.56,57 Patients who experienced peripheral neuropathy58 during paclitaxel chemotherapy were three times more likely to develop neuropathic pain. In long-term follow-up they had twice as many visits to their healthcare provider and had taken more prescription medications for pain than those without neuropathic pain. While there are published guidelines for the initial treatment of neuropathic pain, including gabapentin, pregabalin, carbamazepine, tricyclic antidepressants, oxycodone, amytriptyline, and others,59 – 62 RCTs have shown that medications such as lamotrigine and gabepentin have no benefit on neuropathic pain.63– 65 Because neuropathic pain is largely resistant to common analgesics,66,67 many patients seek out CAMs.

Sleep disruption is common during active therapy for breast cancer. It may even precede therapy and then persist for many years in survivors. Insomnia may manifest in different ways: difficulty initiating or maintaining sleep, early morning awakening, and poor quality of sleep. It is associated with other problems like daytime somnolence and fatigue. It can be classified as a symptom of malignancy, side effect of treatment, or potentially as a comorbid condition. Up to 51% of patients with breast cancer report sleep difficulties. Of them, 19% meet criteria for insomnia syndrome and 95% will have chronic (more than 6 months duration) problems.82,83 While hypnotic medications are indicated to treat initial symptoms, alternative nonpharmacologic therapies are ideal for chronic insomnia.

Acupuncture

Behavioral Intervention

Several studies examined acupuncture in HIV- and diabetes-related neuropathy68 –71; studies evaluating for chemotherapy-induced peripheral neuropathy are limited. In a case series of five patients with greater than World Health Organization (WHO) grade II chemotherapy-induced peripheral neuropathy,56 all reported an improvement in their average pain scale and in the sensation and movement of treated fingers and toes. All had a reduction in analgesic dosage and tolerated the treatment without adverse effect. RCTs are needed to better understand the role of acupuncture in the treatment of chemotherapy-induced peripheral neuropathy in breast cancer survivors.

Breast cancer survivors with chronic insomnia who received cognitive behavioral therapy (CBT) in eight weekly group sessions experienced better subjective sleep quality, fewer medicated nights, decreased depression and anxiety, and better global QOL compared with matched subjects on a waiting list for CBT.83 These benefits were preserved for up to 12 months following CBT.

Nutrition and Supplements Additionally, vitamins, minerals, and amino acids like vitamin E, glutamine, magnesium, and calcium during chemotherapy are being studied for both treatment and prevention of peripheral neuropathy.72–74 In a prevention study, patient-reported symptoms improved compared to a control arm when they received glutamine with chemotherapy. However, a difference in nerve conduction studies was not appreciated between the two groups. While calcium and magnesium infusions with chemotherapy may prevent peripheral neuropathy, studies are needed to determine whether these may affect the chemotherapeutic efficacy before they can be routinely recommended.56,75–79 Finally, two small studies evaluated intravenous acetyl-L-carnitine

INSOMNIA

COGNITIVE DEFICITS There has been increasing concern about the effect of chemotherapy on cognitive function. Cross-sectional studies suggested that women treated with chemotherapy develop a cognitive decline, specifically in memory, executive and visuospatial functioning, information processing speed, attention, and learning.84 – 86 Some longitudinal studies have not confirmed these results.87–90 These suggested that breast cancer patients treated with chemotherapy suffer from motor slowing like neuropathy, and it is unclear how this affects cognitive functioning. Further studies need to be performed to better understand how and whether chemotherapy affects cognitive functioning. Supplementation with vitamin D (in vitamin D– deficient patients) and the use of docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), and omega 3 fatty acids may improve cognitive functioning.91–95 This is still under investigation and initial results only apply to the general population. These supplements may help

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Table 2. CAM Therapies for Symptom Management in Breast Cancer Survivors

Symptom

Published CAM Therapeutic Interventions

Evidence From RCTs Demonstrating the CAM Therapy Is Effective Physical exercise, acupuncture

References

Fatigue

Fish oil, coenzyme Q10, guarana, melatonin, physical exercise, acupuncture

42–45

Hot flashes

Soy products, black cohosh, vitamin E, Acupuncture* homeopathy, acupuncture, self-hypnosis, stellate ganglion block, magnesium, paced breathing

31

Insomnia

Cognitive behavioral therapy

Cognitive behavioral therapy

83

Neuropathy

Acupuncture, vitamin E, glutamine, calcium, magnesium, acetyl L-carnitine

Arthralgias

Acupuncture

Acupuncture

52

Quality of life changes

Mindfulness-based stress reduction (MBSR), reflexology, massage, art therapy, yoga

MBSR, yoga

96,97,104

*Both positive and negative RCTs for the intervention exist.

breast cancer survivors with cognitive deficits or memory impairment.

More women are surviving breast cancer. The disease itself and many of the sequelae may impair overall health-related QOL. While pharmacologic agents help with some QOL domains like depression and anxiety, many patients are opting for nonpharmacologic therapies.

68% completing the therapy) resulted in significant improvements in QOL by standardized scales and improvements in emotional and functional domains, social and emotional roles, and mental health scores. There was also improvement in morning cortisol levels and resting heart rates at the end of the 20-week program.99 Finally, other investigators examined the utility of reflexology, massage, and art therapy on healthrelated QOL.100 –102 These small studies suggest that these interventions also may improve QOL in breast cancer survivors, although evidence is limited.

Behavioral Interventions

Yoga

Mindfulness-based stress reduction (MBSR) is a relatively standardized intervention with benefits in a wide array of measures of physical and mental health. Several studies on the stress-reducing effects have been conducted in breast cancer survivors. These women reported higher energy levels after a 6- or 8-week MBSR program compared to usual care. This may be due to concurrent lowering in depression, anxiety, and fear of recurrence scores, and improved physical function.96 –98 In several studies, the adherence rates were greater than 90%.96 Ongoing studies are evaluating the combination of mindfulness and exercise on QOL. Other self-healing type programs in which there is a focus on stress symptoms like fear, avoidance, and intrusive thoughts have evaluated QOL and biologic endpoints such as serum cortisol levels. In a pilot study, a 20-week self-healing program (N ⫽ 68 patients with

Research on the effects of restorative yoga on overall health-related QOL and biologic markers of stress continues.103–105 A pilot study reported on 51 cancer survivors (37 ovarian, 14 breast) participating in 10 weekly 75-minute restorative yoga classes.103 Healthrelated QOL improved between baseline and the 2-month follow-up. A subsequent study specifically in breast cancer survivors (33% were on active therapy) demonstrated improvements in mental health, depression, and positive affect.104 Yoga compared with supportive care during radiation therapy resulted in improvements in morning salivary cortisol levels (P ⫽ .009) and pooled mean cortisol levels (P ⫽ .03).105 Based on these studies,106,107 restorative yoga may be beneficial for breast cancer survivors in improving overall health-related QOL and decreasing sleep disturbances and fatigue.

QUALITY OF LIFE

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Diet An abundance of data suggest that people who have a high intake of fruits and vegetables are less likely to develop cancer.108 –110 Data on specific dietary approaches for cancer prevention and cancer recurrence are less clear. However, a diet that emphasizes eating fruits, vegetables, grains, and legumes that are close to their natural form will provide nutrients and fiber needed for overall good health.

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SUMMARY The requests for and use of nonpharmacologic interventions and CAM in cancer patients is increasing. Given the large number of breast cancer survivors and the symptoms they endure, it is important for physicians to encourage a diet rich in fruits and vegetables and low in fat, while also being aware of the evidence to support nonpharmacologic therapies for symptoms. Several studies evaluating such interventions have demonstrated significant improvement in overall QOL. For the commonly experienced symptoms of hot flashes, fatigue, and arthralgias, the literature supporting these therapies is limited but growing, and RCTs are needed to better define their role in symptom management for breast cancer survivors.

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