ILLUSTRATIVE CASE SERIES

Managing Chemotherapy-induced 'Hot Flashes'

By Jerome W. Yates, MD, Hematology/Immunology Unit, National Institute on Aging, NIH. Dr. Yates reports no financial relationships relevant to this field of study.

A 48-year-old woman, who is 8 years post-hysterectomy for excessive menstrual bleeding, just completed a four-cycle course of chemotherapy (doxorubicin and cyclophosphamide), for a 2.8 cm, high-grade breast cancer with a negative sentinel node biopsy. She experienced an abrupt menopause with severe vasomotor instability following the second cycle of this therapy. Currently, she complains that she is having up to 40 hot flashes per day, which she documents in a diary, and the most distressing are those that occur at night. She awakens at least 5 to 10 times each night with severe sweats and sleeps less than 2 hours between these episodes. As a result, she feels she is unable to function effectively at home or at work where she is an English teacher. She says the burden of repetitive hot flashes interferes with her family, social relationships, and work effectiveness. She has tried non-hormonal interventions that range from relaxation techniques to nonprescription medications, without achieving relief. Her oncologist is considering placing her on antidepressant medication and has discussed with her the risks of recurrent breast cancer countered by the probable quality-of-life benefits she might experience with hormone replacement therapy.

Discussion

Abrupt chemotherapy-induced menopause results in more severe vasomotor instability (hot flashes) than occur with a more gradual normal menopause.1 Frequent "night sweats" compromise sleep patterns in 10-20% of chemotherapy-treated premenopausal breast cancer patients, and this can lead to a major clinical depression and chronic fatigue.2 A variety of pharmacologic interventions — including venlafaxine and gabapentin, alternative dietary supplements, acupuncture, and stress management techniques — all have been generally disappointing in the control of marked vasomotor instability. The most effective available treatment is hormone replacement therapy: estrogen alone and estrogen with progesterone. Multiple cohort studies provide evidence that both new and recurrent breast cancers may be caused by exogenous estrogen exposure. The validity of these conclusions is open to question because they were not randomized, controlled studies. Cohort, case-control, cross-sectional studies all carry the risk of significant selection bias, which is the one type of bias that is difficult to correct by statistical manipulation. Prospective randomized studies have the advantage of eliminating or minimizing selection bias.

The Women's Health Initiative (WHI) was a randomized trial comparing estrogen alone vs placebo in women 50-79 years of age who had undergone a hysterectomy in an effort to assess estrogen impact on osteoporosis or cardiovascular disease.3 This is the only large, randomized, long-term, placebo-controlled trial of hormonal therapy in postmenopausal women. After a median follow-up of approximately 12 years, it was noted there was a lower incidence of invasive breast cancer in the estrogen-treated group compared with the placebo group. Similarly, there was a reduction in death attributable to breast cancer in the group that received estrogen. In addition, the all-cause mortality following a breast cancer diagnosis was significantly less in the estrogen-treated group. Analyses of subgroups indicate that individuals with known risk factors for developing breast cancer may not experience a cancer reduction following treatment with estrogen. The WHI results suggest that estrogen treatment alone in women with a history of a hysterectomy may prevent breast cancer for those with normal risk profile, which is in conflict with reports from other studies.4,5 Information from a parallel WHI randomized trial of estrogen plus medroxyprogesterone acetate increased breast cancer incidence and attributable mortality, which is consistent with other cohort studies.6

For 70 years it has been noted that pharmacologic doses of estrogens in metastatic breast cancer have yielded durable remissions, most probably the result of concentrations of estrogen far in excess of normal physiologic doses to which breast cancer cells rapidly develop a resistance.7 In the WHI report by Anderson, conjugated equine estrogens derived from the urine of pregnant mares consisting of more than 10 different estrogens was used. The WHI study and the observational studies all agree that there is an increased risk of breast cancer with estrogen and progesterone combined hormone replacement therapy. Only the WHI supports estrogen's role in breast cancer prevention with long-term follow-up and an increased risk for new breast cancers with the combination of estrogen and progesterone. Recent newspaper reports have been overzealous in reporting the benefit from estrogen alone while ignoring this as a special case in women with a previous hysterectomy. Such women proved not to be at increased risk for developing endometrial cancer from the estrogen exposure. The North American Menopause Society position suggests "additional research is needed to understand the different effects of ET and EPT and how they apply to individual women."8

The data from the WHI are sufficiently compelling to advise the patient presented earlier that she could benefit from estrogen therapy for symptom relief. Clearly this study offers hope to women without a uterus suffering from severe symptoms accompanying chemotherapy-induced abrupt menopause. Whether women at normal risk for breast cancer who have severe menopausal symptoms and an intact uterus could or should be treated with estrogens alone for a finite time (e.g., < 6 months) is a research question. A more gradual menopause causes less vasomotor instability and such an approach, in patients closely followed for signs of endometrial metaplasia, could provide improved supportive care for women with severe menopausal symptoms.

References

1. Gupta P, et al. Menopausal symptoms in women treated for breast cancer: The prevalence and severity of symptoms and their perceived effects on quality of life. Climacteric 2006;9:49-58.

2. Biglia N, et al. Menopause after breast cancer: A survey on breast cancer survivors. Maturitas 2003;45:29-38.

3. Anderson GL, et al. Conjugated equine oestrogen and breast cancer incidence and mortality in postmenopausal women with hysterectomy: Extended follow-up of the Women's Health Initiative randomised, placebo-controlled trial. Lancet Oncol 2012 Mar 6. [Epub ahead of print].

4. Singer CF. Climacteric complaints after breast cancer — Is HRT an option? Breast Care (Basel) 2008;3:204-209.

5. Holmberg L, et al. Increased risk of recurrence after hormone replacement therapy in breast cancer survivors. J Natl Cancer Inst 2008;100:475-482.

6. Prentice RL, et al. Estrogen plus progestin therapy and breast cancer in recently postmenopausal women. Am J Epidemiol 2008;167:1207-1216.

7. Ellis MJ, et al. Lower-dose vs high-dose oral estradiol therapy of hormone receptor-positive, aromatase inhibitor-resistant advanced breast cancer: A phase 2 randomized study. JAMA 2009;302:774-780.

8. The 2012 Hormone Therapy Position Statement of The North American Menopause Society. Menopause 2012;19:257-271.