BREAST CANCER TREATMENT

© 2008 by American Society of Clinical Oncology

Breast Cancer Survivors and Hot Flashes: The Search for Nonhormonal Treatments

1. Nancy E. Avis

+ Author Affiliations

1. Department of Social Sciences and Health Policy, Wake Forest University School of Medicine, Winston-Salem, NC

Hot flashes and night sweats (vasomotor symptoms) are a major problem for survivors of breast cancer.¹ Studies show that hot flashes affect approximately 65% of women after treatment for breast cancer,^1-3 with many women rating them as severe.^2,3 Carpenter et al³ reported that hot flashes were even more prevalent among tamoxifen users (72%) and women treated with chemotherapy (78%). Among premenopausal women who receive both chemotherapy and antiestrogen hormone therapy, the prevalence of vasomotor symptoms can be as great as 90%,⁴ and survivors of breast cancer frequently request relief from hot flashes.⁵ Not only do vasomotor symptoms affect quality of life,^6-8 but they may lead to discontinuation of endocrine therapies such as tamoxifen and aromatase inhibitors. Nonadherence to endocrine therapy has been reported to range from 25% to 55%, with the development of adverse effects being the primary reason for nonadherence.⁹

Estrogen therapy, alone or in combination with progesterone, is currently the gold standard for treatment of vasomotor symptoms. Estrogen therapy, however, is associated with a number of risks (including breast cancer) and is often contraindicated for survivors of and women at high risk for breast cancer.^10,11 Given the risks and adverse effects of estrogen therapy, many women have thus sought nonhormonal alternatives.^12,13 These alternatives include other pharmaceutical agents, herbal or dietary remedies, and mind/body or behavioral therapies. Many of the pharmaceutical agents, as well as herbal and dietary remedies, have limited efficacy or multiple adverse effects.^12,14,15 Given the lack of evidence for and potential adverse effects of these agents, mind-body or behavioral treatments for hot flashes are particularly attractive to survivors of breast cancer.^16,17

Although the pathophysiology of vasomotor symptoms is not well understood, they are believed to be related to a rapid decline or fluctuation in estrogen levels. Current theories suggest that hot flashes can be linked to a disruption in thermoregulation and that elevated levels of brain norepinephrine, which narrow the thermoneutral zone, may be the primary mechanism of action for altered thermoregulation.^18-20 If elevated sympathetic activity is related to this thermoneutral zone and hot flashes, then mind-body techniques that reduce this activity may help reduce hot flashes. Mind-body interventions include treatments such as paced respiration, biofeedback, relaxation, meditation, yoga, mindfulness-based stress reduction, and hypnosis.

Additional evidence for the possible benefit of mind-body interventions comes from the literature pertaining to stress and anxiety. Stress and anxiety may contribute to the frequency and intensity of symptoms.^21-27 A 6-year longitudinal analysis from the Study of Women's Health Across the Nation found that baseline anxiety conferred a three-fold increased risk of vasomotor symptoms.²⁸ Thus behavioral relaxation techniques that reduce a woman's stress or anxiety may provide relief from hot flashes.

The study by Elkins et al²⁹ reported in this issue of the Journal of Clinical Oncology examines the effectiveness of hypnosis for the treatment of hot flashes. In this study, 60 female breast cancer survivors were randomly assigned to receive hypnosis five times a week or no treatment. The intervention group showed an impressive reduction of 62% in a hot flash score (frequency times severity), as well as reductions in hot flash interference, sleep problems, anxiety, and depression. The no-treatment control group showed little improvement. A limitation of the study, however, is the lack of a placebo control. A substantial placebo effect found in other studies of hot flashes³⁰ suggests that attention alone or expectancies on the part of study participants may be sufficient to reduce hot flashes. The authors recognize this limitation and state that it is being addressed in future research.

The selection of appropriate control groups is a particular challenge in the area of mind-body interventions. Mind-body interventions in general show promise for alleviating hot flashes, but many studies have methodologic problems, such as small sample sizes, nonrandomized designs, or inadequate control groups. Relaxation training or paced respiration, which involves slow, deep, abdominal breathing, has shown some promise as an effective intervention for hot flashes in several small studies,^31-35 but only two of these studies had an attention control group.^31,34 One small study with patients with breast cancer randomly assigned to receive applied relaxation or electro-acupuncture found a significant decrease in hot flashes in both groups, but there was no control group.³⁶

Yoga has also been considered as a possible treatment for vasomotor symptoms. Two small pilot studies of yoga show promise, but lack any control groups. Cohen et al (2007) conducted an uncontrolled study of 14 postmenopausal women who participated in eight weekly 90-minute sessions of restorative yoga and showed a decrease of 30.8% in mean number of hot flashes.³⁷ In another uncontrolled study of Hatha yoga among 12 peri- or postmenopausal women, significant pre- to post-treatment improvements were found for severity of menopausal symptoms, hot flash daily interference, and sleep disturbances, as well as improved sleep quality.³⁸ Frequency of hot flashes only showed a small decrease.

Several multimodal interventions involving cognitive-behavioral treatment and relaxation have shown promise, but are also mixed with respect to adequate controls.^39-41 Hunter and Liao⁴¹ compared a four-session cognitive-behavioral treatment, hormone therapy, and no treatment among women experiencing hot flashes and found that both the cognitive-behavioral treatment and hormone therapy groups significantly reduced hot flash frequency. A small study (N = 29) using a multimodal approach found that women randomly assigned to an intervention of 8 weekly sessions of psychoeducation, cognitive restructuring, and paced respiration showed significant reduction in hot flashes, whereas a wait-list control group showed a much smaller reduction.³⁹ One of the largest studies (N = 76) focused specifically on breast cancer survivors and randomly assigned women to a tailored intervention that included pharmacologic and paced respiration as appropriate or usual care.⁴⁰ Patients who received the tailored intervention showed statistically significant improvement in menopausal symptoms over usual care. These studies, however, lack a placebo or attention control condition.

These mind-body and behavioral approaches to reducing vasomotor symptoms are attractive interventions for survivors of breast cancer. They convey minimal or no risk, have no adverse adverse effects, and are generally low cost. However, they present particular challenges to researchers. Many of the studies in the literature suffer from small sample sizes, lack adequate control groups, or report poor adherence. Identifying appropriate control groups is a major challenge for these interventions. Study participants generally enroll with the expectation of a beneficial effect, and the placebo effect can be strong. Research designs should ideally include an attention control group that receives the same amount of contact time as the group receiving the active intervention. The control group intervention should be credible enough so that participants can believe in its effectiveness while also being sufficiently different from the intervention of interest. Although blinding of intervention providers is difficult, study participants need to be unaware of which group is the active treatment. Protocol adherence and study retention are other challenges. Mind-body studies require a high degree of commitment by study participants and tend to have a smaller effect on hot flashes than estrogen therapy. Many studies have high drop-out rates when participants do not see a benefit or find the intervention too time intensive. Reducing logistical barriers and creative approaches to retention are required.

Despite the challenges, it is important to continue investigating safe approaches to alleviating these disturbing symptoms for breast cancer survivors. Guidelines from the American Society of Clinical Oncology⁴² and the National Comprehensive Cancer Network⁴³ now recommend that optimal adjuvant hormonal therapy for postmenopausal women with hormone receptor–positive breast cancer include an aromatase inhibitor for up to 5 years as initial therapy for post–tamoxifen treatment. Adverse events and adverse effects such as vasomotor symptoms are the main reason for nonadherence to endocrine treatment, and interventions aimed at reducing adverse adverse effects are needed. Mind-body approaches provide potentially safe and effective interventions to reduce vasomotor symptoms and are particularly appropriate for survivors of breast cancer.