Functional status is well maintained in older women during adjuvant chemotherapy for breast cancer

J. M. Watters1,2,+, J. C. Yau3,§, K. O’Rourke1,4,, E. Tomiak3 and S. Z. Gertler3

1 Department of Surgery, 2 Ottawa Health Research Institute, 3 Ottawa Regional Cancer Centre, 4 Clinical Epidemiology Unit, Ottawa Hospital; Ottawa, Canada

Received 11 February 2003; revised 19 June 2003; accepted 12 August 2003


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background:

While adjuvant chemotherapy is known to improve survival in older women with breast cancer, there is little information about its effects on physical function and health-related quality of life.

Patients and methods:

‘Young’ (<65 years of age) and ‘older’ (>=65 years of age) postmenopausal women completed the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core Module (QLQ-C30) and BR23 questionnaires and other measures prior to, during and at the completion of anthracycline-based adjuvant chemotherapy, and then 6 and 12 months later.

Results:

Physical, role and social function decreased during chemotherapy and emotional function improved (all P <0.01). The decline in physical function was more marked in young (age range 31–64 years; n = 45) than in older women (65–80 years; n = 20) (P <0.05), despite similar baseline values and drug dose intensities. Physical and role function had recovered at 6 months post-chemotherapy. Older patients had consistently better emotional function (P <0.01).

Conclusions:

Physical function and other functional domains are impaired in postmenopausal women during adjuvant chemotherapy for breast cancer, but recover subsequently. Physical function appeared to be better maintained in the older women, who tolerated adjuvant chemotherapy well overall. A knowledge of these effects is important for clinical decision-making and when defining social support needs during adjuvant chemotherapy.

Key words: adjuvant therapy, breast cancer, elderly, health-related quality of life, physical function


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Older women bear a considerable part of the burden of breast cancer. More than one-half of new cases of breast cancer in Canada occur in women aged >=60 years and nearly one-third in women >=70 years [1]. Survival is improved by adjuvant chemotherapy, but little information is available about other outcomes, such as health-related quality-of-life (HR-QoL), which appear to be of particular interest to older patients [26]. Muscle mass, strength and functional status tend to decline with increasing age, and we postulated that older women would suffer more marked declines in strength and physical function during adjuvant chemotherapy [7]. Our purpose was to evaluate physical function, other functional domains and strength in postmenopausal women receiving adjuvant chemotherapy for breast cancer, and to compare them in women aged 65 or older with those in younger women. We limited the study to postmenopausal women to minimise potential confounding effects of chemotherapy-induced menopause and of menopausal status on HR-QoL [8].


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
We conducted a prospective cohort study in postmenopausal women receiving anthracycline-based adjuvant chemotherapy for breast cancer at the Ottawa Regional Cancer Centre. Postmenopausal women referred for consideration of and offered anthracycline-based adjuvant chemotherapy were identified in the practices of three of the centre’s medical oncologists. The study was reviewed and approved by the hospital’s research ethics board. All patients gave written consent. Chemotherapy was planned as six cycles of 5-fluorouracil 500 mg/m2 i.v. on days 1 and 3, doxorubicin 50 mg/m2 on day 1 and cyclophosphamide 500 mg/m2 i.v. on day 1, at 21 day intervals. Any subsequent alterations were determined in accordance with normal clinical practice.

Physical function and other HR-QoL domains were assessed using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core Module (QLQ-C30, version 2.0), which patients completed prior to chemotherapy (baseline), immediately before the third cycle, 3 weeks after the sixth cycle and 6 (follow-up) and 12 months later [9, 10]. In addition to the cancer-specific QLQ-C30, we employed a site-specific instrument (QLQ-BR23 breast cancer module [11]), a generic instrument (SF-36 Health Survey; English Canadian, Medical Outcomes Trust, Boston, MA, USA) and a domain-specific instrument [Karnofsky performance status (KPS)]. Maximal voluntary handgrip strength was evaluated at the same times, taken as the highest of three brief, maximal contractions in the dominant hand, 30–60 s apart, using a handgrip dynamometer (Digital Pinch/Grip Analyser; MIE Medical Research, Leeds, UK) [12].

Age was treated as a dichotomous variable with a cut-off point of 65 years [13]. The effects of adjuvant chemotherapy were evaluated by comparing baseline values with those at completion of chemotherapy, when the magnitude of adverse effects was anticipated to be greatest. Subsequent recovery was evaluated by comparing baseline with post-chemotherapy values at 6 month, by which time recovery was expected. Other time points were of secondary interest, with less focused expectations, and formal repeated measures analysis was not carried out. Data were robustly analysed using Student’s t-test with additional multivariate and sensitivity analyses, and are reported as mean ± standard deviation.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Of the 65 patients studied, 45 were <65 years of age (‘young’) and 20 patients were >=65 years of age (‘older’). Sixty-five of 68 patients identified agreed to participate. Five patients (four, young; one, older) were known to have developed recurrence (two patients) or serious comorbidity (stroke, one patient), or to have moved elsewhere (two patients). Data at 6 and 12 months post-chemotherapy did not appear to differ significantly (data not shown). Drug–dose intensities, nodal status and the use of breast-conserving surgery, radiotherapy and adjuvant tamoxifen were similar in young and older women (Table 1).


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Table 1. Characteristics of ‘young’ (<65 years of age) and ‘older’ (>=65 years of age) patients
 
All women
QLQ-C30 physical function, role function, social function and global health status were lower at the completion of chemotherapy than at baseline, and fatigue had increased (all P <0.01) (Table 2). The mean decline in physical function was such as would be perceived by patients as a ‘moderate’ change [14]. Emotional function had improved by the completion of chemotherapy (P <0.01). There was no significant change in cognitive function from baseline to completion of therapy (95% confidence intervals –10 to 1; P = 0.11). At follow-up, physical, role and cognitive function and global health status were similar to baseline values, whereas social (P <0.05) and emotional function (P = 0.05) were better.


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Table 2. EORTC Quality of Life Questionnaire Core Module (QLQ-C30)
 
Body image (QLQ-BR23) was rated lower at the completion of chemotherapy than at baseline (P <0.001), whereas sexual function and enjoyment did not change and future perspective improved (P <0.05) (Table 3). At follow-up, body image, sexual function and sexual enjoyment did not differ from baseline values; future perspective was significantly better than at baseline (P <0.001).


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Table 3. EORTC QLQ-BR23 breast cancer module
 
SF-36 physical function (P <0.01), role function–physical (P <0.05) and vitality (P <0.001) were lower at the completion of chemotherapy than at baseline (Supplementary data Table 1 is available at Annals of Oncology on-line). Mental health and role function–emotional had improved by the completion of therapy (both P <0.05). At follow-up, physical function, general health, vitality and mental health did not appear to differ from baseline values, whereas role function–physical and role function–emotional (both P <0.01) were better than baseline. Bodily pain did not change during therapy or follow-up. Social function at the completion of chemotherapy was not different from baseline, but was higher than baseline at follow-up (P <0.05). KPS declined significantly by the completion of chemotherapy (92 ± 6 versus 85 ± 11; P <0.001), but did not differ from baseline at follow-up.

Young versus older women
Baseline QLQ-C30 physical, role, social and cognitive function, global health status, fatigue, and nausea and vomiting were similar in both age groups. Emotional function was better in older women at baseline and throughout the study (both P <0.02). The mean decline in physical function with chemotherapy was more marked in young (–18 ± 19) than older women (–4 ± 16; P = 0.02) (Figure 1 and Supplementary data Figure 1, which is available at Annals of Oncology on-line). The declines in role function, social function and global health status, the improvement in emotional function, and levels of fatigue with chemotherapy were similar in young and older women. Older women reported less nausea and vomiting during chemotherapy (P <0.05). The improvements in social and emotional function at follow-up relative to baseline did not appear to differ between young and older women.



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Figure 1. Mean change in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core Module (QLQ-C30) physical function scale scores in ‘young’ (<65 years of age) and ‘older’ (>=65 years of age) women.

 
At baseline, QLQ-BR23 body image and sexual enjoyment were rated similarly by young and older women, sexual function better by young women (P <0.05) and future perspective better by older women (P <0.05). The decline in body image by the completion of chemotherapy tended to be more marked in young women (P = 0.06). The improvement in future perspective at follow-up was greater in young women (P <0.05), at which time it appeared to be similar in young and older women.

Baseline SF-36 physical function, role function–physical, role function–emotional, vitality, general health and bodily pain were similar in young and older women. Baseline social function (P <0.05) and mental health (P <0.001) were rated higher by older women. Physical function, role function–physical and vitality declined and role function–emotional and mental health improved during chemotherapy to similar extents in young and older women. The improvements in role function–physical (P <0.05) and role function–emotional (P = 0.05) at follow-up relative to baseline appeared greater in young women.

Baseline KPS and the decline during chemotherapy appeared similar in young and older women. Handgrip strength was lower in older than in young women at baseline (20 ± 4 versus 23 ± 4 kg; P <0.02), but did not change during chemotherapy or follow-up.

The study was observational out of necessity, and as a consequence, the groups to be compared were expected to differ in terms of baseline covariates. We sought to address the possible influence of these covariates on changes in physical function using multivariate techniques. Multiple linear regression analysis including a subset of measured covariates chosen as clinically relevant suggested that the age effect was still present. However, confidence in the robustness of this analysis is limited by the small group sizes. Since methods of imputation of missing values require large samples in order to be reliable, we employed sensitivity analysis with respect to change in physical function. Assuming extreme values (i.e. that physical function in young patients with missing values was optimal and in older patients was poor), the preservation of physical function in older relative to young patients was no longer apparent.


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The management of breast cancer varies in relation to patient age, reflecting a decreased use of therapeutic modalities in older women. Moreover, the care of older women is less likely to be consistent with clinical guidelines and consensus recommendations [15, 16]. Older women are a heterogeneous population. It is to be expected that the management of breast cancer will reflect factors such as the presence of significant comorbidity and that the treatment choices made by older women may well differ from those of younger women. However, comorbidity does not appear to account fully for age-related variation in treatment, and there is evidence of age bias in referral to medical oncologists and in the presentation of treatment options to older patients [1719]. Presumably such bias reflects questions about the efficacy of adjuvant therapy in older women and/or an anticipation of greater adverse effects. Although older women have been under-represented in clinical trials, the survival benefit associated with anthracycline-containing regimens of adjuvant chemotherapy appears similar to that in younger women [2, 20]. Outcomes other than the traditional ones of survival, response rates and disease-free intervals appear to be of particular importance to older patients [3, 4]. For example, they are reported to be more concerned about the effects of therapy than are young patients, and may be less willing to trade current QoL for potential improvements in survival [5, 6, 21]. Clinically significant treatment toxicity and resultant hospitalizations were no more frequent in older patients in two recent reports [22, 23]. However, there is little information about whether HR-QoL outcomes differ in older patients. Patterns of care might be altered significantly if adjuvant chemotherapy were known to be well tolerated by older women.

Body composition tends to change in a predictable manner during adult life, the most substantial alteration being a decline in muscle mass of as much as 40–50% by the eighth decade of life relative to young adulthood [24]. More or less parallel changes occur in strength, and age-related differences in muscle fibre types and numbers of functioning motor units and changes in muscle energetics have been identified [25, 26]. In previous work, we have observed that older patients were substantially weaker than young patients following major elective surgery and their recovery of strength was impaired [12]. Thus we postulated that older women with breast cancer would experience more marked declines in strength and physical function during the stress of adjuvant chemotherapy.

When data for all women were combined, physical function declined during adjuvant chemotherapy, as did role function, social function and global health status. The magnitude of the impairments was at a level that would be perceived by patients as ‘moderate’ (for physical and role function] or ‘a little’ (for social function and global health status) [14]. Importantly, by 6 months post-chemotherapy each had returned to or was better than baseline values. Moreover, emotional function improved throughout chemotherapy and the period of follow-up. A knowledge of the burden for patients represented by these changes, and that they resolve following therapy, is relevant for clinicians and patients in deciding about adjuvant chemotherapy. It may be also useful in planning treatment, for example, in defining social support needs.

The older women in this study reported a decline in physical function which was considerably less marked despite receiving chemotherapy at dose intensities similar to those in the young women. Furthermore, they rated their emotional function higher than did young women throughout therapy and follow-up, and declines in other functional domains were no worse than those in young postmenopausal women. Others have identified a negative correlation between age and psychological distress following breast cancer treatment and suggested that younger women have greater difficulty adjusting [27]. From the perspective of physical function and other functional domains, the older women tolerated adjuvant chemotherapy at least as well as younger women, supporting the concept that age should not be used in isolation in decision-making about adjuvant chemotherapy for breast cancer. Other possible predictors of adverse functional outcomes remain to be examined in larger patient groups; for example, comorbidity and baseline emotional function. Instruments that evaluate physical and/or instrumental activities of daily living, nutritional status and other elements of a comprehensive geriatric assessment may have predictive value.

Our observations are not generalizable to all older women with breast cancer. The number studied is small and it is likely that they were selected for medical oncology referral and offered adjuvant chemotherapy because they were particularly fit. The observation that baseline function in most domains was similar in both age groups is consistent with a selection bias, although we do not have information about women who were not referred for, or offered, adjuvant chemotherapy, or who were offered it but declined. Explanations for our observations other than selection bias may also be relevant. The difference in decline in physical function during chemotherapy may reflect a difference in the health expectations of young and older women and a discordance between their health expectations and current experience [28]. Specifically, individuals may experience a substantial impact on their QoL from a modest clinical condition if they have high expectations of their health, whereas those whose expectations of their health are lower (e.g. older patients) may experience less deterioration in the same circumstances. The elderly expect some deterioration in physical function as a consequence of their advancing age, yet may be quite satisfied despite limited functioning [29, 30]. Many elderly persons appear to view success in aging as a process of adaptation rather than as a state of being or function [31].

We conclude that anthracycline-based adjuvant chemotherapy for breast cancer in postmenopausal women is accompanied by impairments in physical function and other functional domains which are mild to moderate in degree and recover by 6 months post-therapy. Selected older women tolerate such therapy well. Age should not be used in isolation in decision-making about adjuvant chemotherapy for breast cancer.


    Acknowledgements
 
The authors wish to acknowledge the contribution of Susan M. Kirkpatrick. This work was supported by Canadian Breast Cancer Research Initiative grant No. 009291.


    Footnotes
 
+ Correspondence to: Dr J. M. Watters, Ottawa Hospital (Civic Site), 737 Parkdale Avenue, Ottawa, Ontario, Canada K1Y 1J8. Tel: +1-613-761-4780; Fax: +1-613-761-4698; E-mail: jwatters{at}ohri.ca Back

§ Present address: Northwestern Ontario Regional Cancer Centre, 290 Munro Street, Thunder Bay, Ontario, Canada P7A 7T1. Back

Present address: Centre for Statistics in Medicine, Institute of Health Sciences, Old Road, Headington, Oxford OX3 7LF, UK. Back


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