Severe Menopausal Symptoms Are Widespread among Survivors of Breast Cancer Treatment Regardless of Time Since Diagnosis

Abstract

Background:

The intensity and persistence of treatment-related symptoms among breast cancer survivors is incompletely understood.

Objective:

The objective of the study was to estimate prevalence of severe symptoms well after initial treatment for breast cancer, to test whether symptom intensity diminishes with time or varies by treatment received.

Design, setting, subjects:

This was a cross-sectional survey of female survivors of stage I-III invasive breast cancer, seen for routine follow-up a year or more after diagnosis.

Measurements:

Data was derived from three validated questionnaires indicating physical and emotional domains. Symptoms rated in the top two levels of four- or five-item Likert scales were “severe.” Associations with symptom intensity were tested using multivariate linear regression.

Results:

Survey response was 68.5% (50/73). Respondents were age 55.4 (±9.1) years, median 2.2 (1.0–13.1) years since diagnosis; 64% were receiving endocrine therapy. Severe levels of hot flashes (42% of respondents), weight gain (32%), low libido (32%), and joint pain (30%) were common; (36%) of respondents rated sleep “fairly poor” or “very bad;” 30% were fatigued at least half the day. For 34%, health typically limited vigorous activities “a lot.” Most (84%) respondents were experiencing at least one severe symptom. Symptom intensity did not vary with time since diagnosis. Of seven symptoms, three (hot flashes, weight gain, low libido) were more intense when systemic treatment had included endocrine therapy. Time in past month feeling down, nervous, or worn out increased with intensity of physical symptoms.

Conclusions:

Given their severity, persistence, and association with emotional burden, treatment-related symptoms among breast cancer survivors (BCS) merit greater attention toward clinical management, patient education, and longitudinal study.

Introduction

It is projected that by 2020 there will be 5.8 million breast cancer survivors (BCS).¹ Despite the large number of published clinical trials, data on the adverse effects of breast cancer therapies remain limited in several ways. First, clinical trials usually report acute toxicities only. Yet it is increasingly recognized that adverse effects may persist long after cancer treatment.^2–5 Second, adverse event data for clinical trials are usually recorded by the physician, yielding symptom frequencies lower than when patients self-report using a questionnaire.⁶ Finally, few studies of BCS report on the intensity of symptoms.^7,8 Such symptoms are often severe. Of BCS who reported experiencing since their cancer diagnosis a physical or emotional problem related to menopause, 50% felt the problem required treatment.⁸ For the current study, therefore, we surveyed BCS who were one year or more beyond diagnosis to learn about the intensity of their symptoms. We investigated whether symptoms decrease in intensity with time since diagnosis or are associated with type of treatment. We also explored correlations between physical symptoms and emotional burdens.

Methods

Female breast cancer survivors were eligible for this study if they had completed surgery, radiation, and/or chemotherapy, were at least 12 months beyond the initial diagnosis of stage I-III invasive cancer, and were being seen for routine follow-up by a single treating medical oncologist (JM). Patients were eligible for study even if they were receiving endocrine therapy. Patients not literate in English were excluded from the study.

During July 2010 to April 2011, all eligible patients were approached for informed consent to complete a written survey about their physical and emotional symptoms. The questionnaire, filled out in clinic or at home, was assembled from physical and emotional subscales of three validated quality of life instruments (FACT-B, SF-36, HADS).^9–11 Because our survey was not undertaken to study quality of life, it was unnecessary to administer the source instruments in their entirety.

If a subject left a symptom-specific question unanswered, she was assumed to have experienced little of the problem being assessed, with the following exceptions. Missing level of sleep quality in the past month was imputed from reported fatigue in the past week or feeling tired or worn out in the past month; missing level of fatigue was imputed from reported sleep quality; however, missing levels of bodily pain and of pain in the joints could not be imputed from other symptoms. Body mass index (BMI) was abstracted from records of physical examination conducted at approximately the same date as the survey.

Menopausal symptoms were scored on a five-point Likert scale. Those that bothered patients “quite a bit” (4) or “very much” (5) were considered “severe.” For fatigue (scored 0–10), “severe” corresponded to a minimum rating of 5, “at least half the day.” For sleep quality (four-point scale), “severe” corresponded to a rating of 3, “fairly poor” or 4, “very bad.” For limitation in vigorous activities (three-point scale), “severe” corresponded to 3, “limited a lot.” Feelings in the past month were scored as present from 1, “all,” to 6, “none” of the time.

The primary risk factor, time since diagnosis, was tested in linear regression models of symptom intensity. The sample provided over 80% power to detect (with two-sided testing, alpha=0.05) a correlation as low as 0.37. In the models of physical symptoms, time since diagnosis was tested with and without logarithmic transformation; a quadratic term was also tried. In exploratory analysis, correlation between intensity of each physical symptom and time in adverse emotional states was evaluated using univariate linear regression.

Results

Survey response

Of eligible patients approached (n=73), all consented and 50 (68.5%; see Table 1) returned a questionnaire. Respondents and nonrespondents did not differ significantly in stage of disease, past radiation and systemic treatment, current use of endocrine therapy, months since diagnosis, current age, and age at diagnosis (data not shown).

Table 1.

Characteristics of Survey Respondents (N=50)

	Mean (±SD) or median (5th–95th percentile)
Age at study (years)	55.4 (±9.1)
Age at diagnosis (years)	52.0 (±9.4)
Time from diagnosis (months)	25.8 (13.7–132.3)
Body Mass Index at study	26.5 (20.1–34.9)
Heart rate at study	75.5 (±9.1)

	N (%)
Current menopausal status
Premenopausal	7 (14)
Postmenopausal since treatment	11 (22)
Postmenopausal since before diagnosis	32 (64)
Stage of disease
I	14 (28)
II	29 (58)
III	7 (14)
Radiation treatment
Yes	24 (48)
No	22 (44)
Unknown, external records not available	4 (8)
Systemic treatment
Chemotherapy only	10 (20)
Endocrine therapy only	14 (28)
Both therapies	23 (46)
Current endocrine therapy
Yes	32 (64)
No	18 (36)

Symptoms

Symptoms reported as severe during the past week by over 30% of respondents (see Table 2) were hot flashes, weight gain, low libido, and joint pain. Also during the past week, 30% of subjects were fatigued at least half the day. In the past month, half (25/50) of subjects reported accomplishing less work or regular daily activities than they would have liked, due to physical health (n=21) or emotional problems (n=19), often both (n=15). Over a third rated their quality of sleep as “fairly poor” or “very bad” (see Table 2). A third (34%) of subjects reported that health limited vigorous activities (running, heavy lifting, strenuous sports) “a lot” on a typical day. Far fewer (8%) reported that moderate activities (pushing a vacuum cleaner, bowling, golf) were similarly limited.

Table 2.

Symptoms, Ranked by Prevalence of Severe ^a Symptom

	N respondents	N (%) with symptom	N (%) with severe symptom
Hot flashes	50	41 (82.0)	21 (42.0)
Low libido	45	35 (77.8)	16 (35.6)
Weight gain	46	33 (71.7)	16 (34.8)
Pain in the joints	46	33 (71.7)	15 (32.6)
Night sweats	48	28 (58.3)	13 (27.1)
Vaginal dryness	48	26 (50.0)	13 (27.1)
Dyspareunia	41	19 (46.3)	9 (22.0)
Bodily pain	43	31 (72.1)	9 (20.9)
Irritability	48	26 (54.2)	9 (18.8)
Headaches	47	27 (57.5)	8 (17.0)
Breast sensitivity or tenderness	46	21 (45.6)	8 (17.4)
Mood swings	49	27 (55.1)	8 (16.3)
Bloating	47	20 (42.4)	7 (14.9)
Dizziness	48	22 (46.8)	6 (12.5)
Cold sweats	48	18 (37.5)	4 (8.3)
Upper body swelling^b	48	14 (29.2)	n/a
Vaginal discharge	50	10 (20.0)	2 (4.0)
Vaginal itching	50	8 (16.0)	1 (2.0)

A severe symptom is one that bothered the respondent “quite a bit” or “very much” in the past week, except for bodily pain, where the period surveyed is the past month.

This term encompasses swelling in all areas that may be affected by surgery, not only in the hand, forearm, and arm, but in the chest wall region as well. It was scored only as present or absent.

Overall, 84% (95% CI 70.9%–92.8%) of respondents were experiencing severe levels of at least one of the seven most prevalent symptoms: hot flashes, weight gain, low libido, joint pain, poor sleep, fatigue, limitation in vigorous activities. Over half (52%) (95% CI 37.4%–66.3%) of subjects reported currently having more than one severe symptom in that list.

Association of symptoms with time and treatment

None of the seven most prevalent symptoms varied in intensity with time since diagnosis. Nor did symptoms vary with receipt of chemotherapy, radiation therapy, or current endocrine therapy. However, having received systemic treatment that included endocrine therapy was associated with greater intensity of three symptoms. On the five-point scale, such treatment intensified hot flashes by 1.29 points (95% CI 0.56–2.02; p<0.005), but only if the patient was currently less than three years beyond diagnosis; the latter estimate was adjusted for treatment-associated transition to menopause. Similarly, weight gain was intensified by 1.40 points (95% CI 0.34–2.47; p<0.02), adjusted for current age, intensity of bodily pain in past month, and (log) body mass index; and low libido was intensified by 1.25 points (95% CI 0.29–2.21; p<0.02), adjusted for intensity of dyspareunia.

Correlation between symptoms and emotional states

Time affected by specific emotions during the past month is summarized in Table 3. Intensities of emotional states and physical symptoms were significantly correlated: Figure 1 shows the point increase (95% CI) in emotional burden for every point increase in intensity of menopausal symptom.

Fig. 1.

Symptom intensity is associated with emotional burden. Estimated gains in emotional burden are indicated with triangles, accompanied by corresponding 95% confidence intervals (solid lines).

Table 3.

Frequency of Emotional States during the Past Month

	N respondents	N (%) affected at least “some of the time”	N (%) affected “most or all of the time”
Happy	49	49 (100)	28 (57.1)
Calm and peaceful	48	40 (83.3)	17 (35.4)
Lots of energy	47	32 (68.1)	13 (27.7)
Worn out	46	28 (60.9)	9 (19.6)
Very nervous	50	15 (30.0)	4 (8.0)
Too down in the dumps to be cheered up	47	12 (25.5)	1 (2.1)

Discussion and Implications

Our survey has measured the highest prevalence of severe menopausal symptoms among BCS to date. The most directly comparable survey, of BCS well beyond their initial treatment for breast cancer, was conducted in 1994.⁷ Six symptoms (hot flashes, night sweats, vaginal dryness, dyspareunia, vaginal itching, vaginal discharge) were studied comparably in both surveys. Among severe symptoms, only severe hot flashes differed in frequency between the two studies—42.0% (21/50) in our study versus 21.9% (40/183) in the earlier study, Fisher's exact test, p<0.006. Treatment regimens may have differed between the two surveys, as suggested by their different frequencies of current endocrine therapy (64% in our survey versus 35% in the earlier survey).⁷

Data comparable to ours were also obtained from a five-year, quality-of-life subprotocol of the Arimidex (anastrozole), Tamoxifen, Alone or in Combination (ATAC) trial.¹² As in the current study, the ATAC substudy reported on symptoms that were clinically significant (“quite a bit” or “very much” of a problem). Unlike our sample, the ATAC substudy participants were exclusively postmenopausal at start of breast cancer treatment. Perhaps as a result, ATAC subjects reported substantially lower frequencies of hot flashes, vaginal dryness, weight gain, night sweats, poor sleep, headaches, dizziness, irritability, and moodswings than our subjects did.

We observed no decrease in symptom intensity with time since breast cancer diagnosis. This finding is consistent with a previous report that cancer-specific deficits in health utility (desirability of state of health) and in ability to work do not diminish with time since diagnosis.⁵ According to another study,¹³ prevalence of cancer-related fatigue diminished from 31% after breast cancer surgery to 14% at 12 months after surgery, but was 21% at five years. We observed no rebound in frequency of severe fatigue at five years, but we acknowledge that few of our respondents (n=6) were beyond five years since diagnosis. The survivorship period beyond five years deserves more study.

Of the various breast cancer treatments our subjects had undergone, only systemic treatment that included endocrine therapy was associated with greater symptom intensity. No association with current endocrine therapy was present. The more intense the treatment-related symptoms we studied, the greater the emotional burdens as well. Poor sleep quality and hot flashes most adversely impacted the three adverse feelings we studied.

Incidentally, our study confirmed a prior report that treatment-associated transition to menopause is associated with greater severity of hot flashes.¹⁴ However, in our analysis, the latter association became nonsignificant after controlling for age at diagnosis (positively associated with intensity of hot flashes) and current age (inversely associated with intensity). Age variables confounded the association with transition to menopause, because subjects who had experienced treatment-associated transition to menopause had been primarily age 43–49 at diagnosis and were age 45–55 when surveyed, apparently placing them within the optimal age range for experiencing severe hot flashes, independently of treatment-associated transition to menopause. The currently observed age associations with hot flashes suggest that (1) the older the woman is at diagnosis of breast cancer, the more adversely her endocrine system is affected by the systemic treatment and (2) aging out of the pre- or perimenopausal period reduces the intensity of hot flashes, but mere passage of time since diagnosis does not.

In conclusion, our pilot cross-sectional study suggests that severe menopausal symptoms are more widespread among BCS than previously reported. This finding underscores the need for longitudinal studies of the prevalence, pattern, and intensity of symptoms that persist following treatment for breast cancer. In addition, the prevalence and severity of symptoms we observed suggest that, as previously reported for cancer patients in general,^15,16 few BCS are receiving effective patient education about strategies¹⁷ to mitigate the longterm burdens of cancer treatment.⁵ Given their severity, persistence, and association with emotional burden, treatment-related symptoms of breast cancer survivors deserve greater clinical and research attention from oncologists and specialists in palliative care.¹⁵

Footnotes

Author Disclosure Statement

The authors declare that no competing financial interests exist.

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